Non-steroidal progesterone receptor modulators

ABSTRACT

The present invention relates to non-steroidal progesterone receptor modulators of the general formula I, 
     
       
         
         
             
             
         
       
     
     the use of the progesterone receptor modulators for the manufacture of medicaments, and pharmaceutical compositions which comprise these compounds. 
     The compounds according to the invention are suitable for the therapy and prophylaxis of gynecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 61/006,015 filed Dec. 14, 2007.

The present invention relates to non-steroidal progesterone receptor modulators, a method for their preparation, the use of the progesterone receptor modulators for the manufacture of medicaments, and pharmaceutical compositions which comprise these compounds.

The steroid hormone progesterone controls in a decisive manner the reproductive process in the female body. Progesterone is secreted in large quantities during the cycle and pregnancy respectively by the ovary and the placenta. Progesterone in cooperation with oestrogens brings about cyclic changes in the uterine mucosa (endometrium) during the menstrual cycle. Elevated progesterone levels after ovulation influence the uterine mucosa to convert it into a state permitting nidation of an embryo (blastocyst). During pregnancy, progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue.

It is further known that progesterone inhibits endometrial proliferation by suppressing oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R. M. Brenner, U. Fuhrmann, H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751).

Progesterone and progesterone receptors are also known to play a significant part in pathophysiological processes. Progesterone receptors have been detected in the foci of endometriosis, but also in tumours of the uterus, of the breast and of the CNS. It is further known that uterine leiomyomas grow progesterone-dependently.

The effects of progesterone in the tissues of the genital organs and in other tissues occur through interactions with progesterone receptors which are responsible for the cellular effects.

Progesterone receptor modulators are either pure agonists or inhibit the effect of progesterone partly or completely. Accordingly, substances are defined as pure agonists, partial agonists (selective progesterone receptor modulators=SPRMs) and pure antagonists.

In accordance with the ability of progesterone receptor modulators to display their effect via the progesterone receptor, these compounds have a considerable potential as therapeutic agents for gynaecological and oncological indications and for obstetrics and fertility control.

Pure progesterone receptor antagonists completely inhibit the effect of progesterone on the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit oestrogen effects in the endometrium, as far as complete atrophy. They are therefore particularly suitable for intervening in the female reproductive process, e.g. post-ovulation, in order to prevent nidation of a fertilized egg cell, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and softening (“ripening”) of the cervix, and to induce a great readiness of the myometrium to contract.

A beneficial effect on the pathological event is expected in foci of endometriosis and in tumour tissues which are equipped with progesterone receptors after administration of pure progesterone receptor antagonists. There might be particular advantages for influencing pathological states such as endometriosis or uterine leiomyomas if ovulation inhibition can additionally be achieved by the progesterone receptor antagonists. Ovulation inhibition also dispenses with some of the ovarian hormone production and thus the stimulating effect, deriving from this proportion, on the pathologically altered tissue.

The first progesterone receptor antagonist described, RU 486 (also mifepristone), was followed by the synthesis and characterization of a large number of analogues with progesterone receptor-antagonistic activity of varying strength. Whereas RU 486 also shows an antiglucocorticoid effect in addition to the progesterone receptor-antagonistic effect, compounds synthesized later are notable in particular for a more selective effect as progesterone receptor antagonists.

Besides steroidal compounds such as onapristone or lilopristone, which are notable by comparison with RU 486 for a better dissociation of the progesterone receptor-antagonistic effect and the antiglucocorticoid effect, also known from the literature are various non-steroidal structures whose antagonistic effect on the progesterone receptor is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, non-steroidal compounds disclosed to date have only moderate antagonistic activity compared with the activity of known steroidal structures. The most effective non-steroidal compounds are reported to have in vitro activities which are 10% of the activity of RU 486.

The antiglucocorticoid activity is disadvantageous for therapeutic use, where the inhibition of progesterone receptors is at the forefront of the therapy. An antiglucocorticoid activity causes unwanted side effects at the dosages necessary for therapy. This may prevent administration of a therapeutically worthwhile dose or lead to discontinuation of the treatment.

Partial or complete reduction of the antiglucocorticoid properties is therefore an important precondition for therapy with progesterone receptor antagonists, especially for those indications requiring treatment lasting weeks or months.

In contrast to the pure antagonists, partial progesterone receptor agonists (SPRMs) show a residual agonistic property which may vary in strength. This leads to these substances showing agonistic effects on the progesterone receptor in certain organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess-Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such an organ-specific and dissociated effect may be of therapeutic benefit for the described indications.

It is therefore an object of the present invention to provide further non-steroidal progesterone receptor modulators. These compounds are intended to have a reduced antiglucocorticoid effect and therefore be suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention are additionally intended to be suitable for the therapy and prophylaxis of hormone-dependent tumours, for example of breast, endometrial, ovarian and prostate carcinomas. The compounds are intended furthermore to be suitable for use in female fertility control and for female hormone replacement therapy.

The object is achieved according to the present invention by the provision of non-steroidal compounds of the general formula I

in which

-   -   A is hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl         radical which is optionally mono- or polysubstituted identically         or differently by Z, or else is Z itself, where Z is defined as         follows:         -   cyano, halogen, hydroxyl, nitro, —C(O)R^(b), —C(O)CH₂R^(b),             —C(O)CF₂R^(b), CO₂R^(b), —O—R^(b),         -   —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d),             —OC(O)—NR^(c)R^(d), —C═NOR^(b),         -   —NR^(c)R^(d), PO₃(Rb)₂, —NR^(e)COR^(b), —NR^(e)CSR^(b),             —NR^(e)S(O)R^(b), —NR^(e)S(O)₂R^(b),         -   NR^(e)CONR^(c)R^(d), —NR^(e)COOR^(b),         -   —NR^(e)C(NH)NR^(c)R^(d), —NR^(e)CSNR^(c)R^(d),             —NR^(e)S(O)N^(c)R^(c)R^(d),         -   —NR^(e)S(O)₂NR^(c)R^(d), —S(O)R^(b), —S(O)NR^(c)R^(d),             —S(O)₂R^(b), —S(O)₂CH₂R^(b),         -   —S(O)₂CF₂R^(b), —SO₂OR^(b),         -   —CSNR^(c)R^(d), —CR^(b)(OH)—R^(b) where     -    R^(b) is hydrogen, a C₁-C₆-alkyl, hydroxy-C₁-C₃-alkyl,         C₁-C₃-alkoxy-C₁-C₃-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,         —(CH₂)_(p)C(O)₂H, —(CH₂)_(p)C(O)₂C₁-C₃-alkyl, a 5- to 6-membered         cycloalkyl or heterocycloalkyl radical which is optionally mono-         or disubstituted by a halogen, a C₁-C₃-alkyl, C₁-C₃-alkoxy         radical or a COOR^(b) radical and has 1, 2 or 3 heteroatoms or     -    a phenyl or 3-12-membered heteroaryl radical which is         optionally mono- or disubstituted by a halogen, a C₁-C₃-alkyl,         C₁-C₃-alkoxy radical or a COOR^(b) radical and has 1, 2 or 3         heteroatoms, or a —(CH₂)_(p)—C₆-C₁₂-aryl radical which is         optionally mono- or disubstituted by a halogen, a C₁-C₃-alkyl,         C₁-C₃-alkoxy radical or a COOR^(b) radical     -    or a partly or fully fluorinated C₁-C₃-fluoroalkyl radical or W         and     -    R^(c) and R^(d) are each independently hydrogen, a C₁-C₆-alkyl,         C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl         radical or a 5- to 12-membered heteroaryl radical optionally         substituted by W, a C(O)R^(b) group with the definition of R^(b)         specified above, —S(O)₂C₁-C₃-alkyl, —C(O)C₁-C₃-alkyl or a         hydroxyl group, or together including the nitrogen form a 3- to         7-membered ring which is optionally mono- or disubstituted by a         trifluoromethyl and/or hydroxyl group and which is optionally         extended by O, S or NR^(f) where         -   W is —NR^(g)R^(h) where         -   R^(g) is hydrogen or C₁-C₃-alkyl and         -   R^(h) is hydrogen or C₁-C₃-alkyl or         -   R^(g) and R^(h) together including the nitrogen form a 3- to             7-membered ring which is optionally extended by O, S or             NR^(f) and         -   R^(f) is hydrogen, C₁-C₃-alkyl, C₁-C₃-acyl,             C₁-C₃-alkylsulphonyl or C₁-C₃-alkoxycarbonyl,         -   and         -   where, when         -   R^(c) is a hydroxyl group, R^(d) can only be hydrogen,             C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl             or C₆-C₁₂-aryl which is optionally substituted by W, and             vice versa, and also         -   R^(e) is hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl,             C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl which is             optionally substituted by W,         -   or     -   A is a C₃-C₁₀-cycloalkyl radical or 3-12-membered         heterocycloalkyl radical which is optionally mono- or         polysubstituted identically or differently by M and         -   M is C₁-C₆-alkyl or a —COR^(b), CO₂R^(b), —O—R^(b) or             —NR^(c)R^(d) group, where R^(b), R^(c) and R^(d) are each as             specified above, and     -   R¹ and R² are each independently an unbranched or branched         C₁-C₅-alkyl group which is optionally substituted by Z or,         together with the carbon atom of the chain, form a carbocyclic         or heterocyclic ring which is optionally substituted by Z and         has a total of 3-7 members, where, when         -   A is hydrogen and R¹ is a methyl radical, R² cannot be a             methyl radical or an ethyl radical,         -   A is hydrogen, R¹ and R² cannot together be a ring having             3-4 members,         -   A is a methyl radical, R¹ and R² cannot both be a methyl             radical or, together with the carbon atom of the chain, form             a cyclopropyl ring,     -   R³ is hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,         C₃-C₁₀-cycloalkyl, 3-12-membered heterocycloalkyl radical which         is optionally mono- or polysubstituted identically or         differently by K, or a C₆-C₁₂-aryl or 3-12-membered heteroaryl         radical which is optionally mono-, di or trisubstituted         identically or differently by L, and         -   K is cyano, halogen, hydroxyl, nitro, —C(O)R^(b), CO₂R^(b),             —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d),             —OC(O)—NR^(c)R^(d), —C═NOR^(b), —NR^(c)R^(d) or a             C₃-C₁₀-cycloalkyl, 3-12-membered heterocycloalkyl radical             which is optionally mono- or polysubstituted identically or             differently by M, or a C₆-C₁₂-aryl or 3-12-membered             heteroaryl radical which is optionally mono-, di- or             trisubstituted identically or differently by L, with the             definition of M specified under A, and         -   L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, a partly or             fully fluorinated C₁-C₆-fluoroalkyl, a partly or fully             fluorinated C₁-C₆-fluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,             C₁-C₆-alkoxy-C₁-C₆-alkoxy, a mono- or bicyclic             (CH₂)_(p)—C₃-C₁₀-cycloalkyl, a mono- or bicyclic             3-12-membered (CH₂)_(p)-heterocycloalkyl radical,             (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, a mono- or bicyclic             (CH₂)_(p)—C₆-C₁₂-aryl radical which is optionally             substituted by V, a mono- or bicyclic 3-12-membered             (CH₂)_(p)-heteroaryl radical which is optionally substituted             by V, or             -   —(CH₂)pPO3(Rb)2, —(CH2)pNRcRd, —(CH2)pNReCORb,             -   —(CH2)pNReCSRb, —(CH2)pNReS(O) Rb, —(CH2)pNReS(O)2Rb,             -   —(CH2)pNReCONRcRd, —(CH2)pNReCOORb,             -   —(CH2)pNReC(NH)NRcRd, —(CH2)pNReCSNRcRd,             -   —(CH2)pNReS(O)NRcRd, —(CH2)pNReS(O)₂NRcRd, —(CH2)pCORb,             -   —(CH2)pCSRb, —(CH2)pS(O)Rb, —(CH2)pS(O)(NH)Rb,             -   —(CH2)pS(O)₂Rb,             -   —(CH2)pS(O)₂NRcRd, —(CH2)pSO2ORb, —(CH2)pCO2Rb,             -   —(CH2)pCONRcRd, —(CH2)pCSNRcRd, —(CH2)pORb, —(CH2)pSRb,             -   —(CH2)pCRb(OH)—Rb, —(CH₂)_(p)—C═NOR^(b),             -   —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —O—CH═CH— or                 —(CH₂)_(n+2)—, and the terminal oxygen atoms and/or                 carbon atoms are linked to directly adjacent ring carbon                 atoms, and         -   n is 1 or 2 and         -   p is 0, 1, 2, 3, 4, 5 or 6, and         -   V is cyano, halogen, nitro, —(CH₂)_(p)OR^(b),             —(CH₂)_(p)S(O)₂R^(b), —C(O)R^(b), CO₂R^(b), —O—R^(b),             —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d),             —OC(O)—NR^(c)R^(d), —C═NOR^(b), —(CH₂)_(p)NR^(c)R^(d),             partly or fully fluorinated C₁-C₆-fluoroalkyl or partly or             fully fluorinated C₁-C₆-fluoroalkoxy,     -   X is one oxygen atom or two hydrogen atoms     -   Y is (CH₂)_(m), —C≡C— or —CH═CH— where         -   m=0 or 1,     -   where, when Y is a CH₂ radical, R³ cannot be hydrogen, and     -   R⁴ is a mono- or bicyclic C₆-C₁₂-aryl which is optionally         substituted identically or differently by 2 L, or one of the         following groups mentioned under B or C:

B: 6-Membered/6-Membered Ring Systems

C: 6-Membered/5-Membered Ring Systems

-   -   where     -   R⁵ is hydrogen or C₁-C₄-alkyl, or a partly or fully fluorinated         C₁-C₄-fluoroalkyl,     -   R^(6a) and R^(6b) are each independently hydrogen, C₁-C₄-alkyl         or a partly or fully fluorinated C₁-C₄-fluoroalkyl, or, together         with the ring carbon atom, form a 3- to 6-membered ring,         and the pharmaceutically acceptable salts thereof.

The compounds according to the invention of the general formula I may, owing to the presence of centres of asymmetry, exist as different stereoisomers. Both the racemates and the separate stereoisomers belong to the subject matter of the present invention.

The present invention further includes the novel compounds as active pharmaceutical ingredients, their therapeutic use and pharmaceutical dosage forms which comprise the novel substances.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used to produce a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention may further be used for the treatment and prophylaxis of hormone-dependent tumours such as, for example, for breast, prostate and endometrial carcinoma.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are also suitable for use for female fertility control or for female hormone replacement therapy.

The non-steroidal compounds according to the invention of the general formula I have strong antagonistic effects on the progesterone receptor with high potency. They show a strong dissociation of effects in relation to their strength of binding to the progesterone receptor and to the glucocorticoid receptor. Whereas known progesterone receptor antagonists such as mifepristone (RU 486) show, besides the desired high binding affinity for the progesterone receptor, likewise a high affinity for the glucocorticoid receptor, the compounds according to the invention are notable for a very low glucocorticoid receptor binding with simultaneously a high progesterone receptor affinity.

The substituents, defined as groups, of the compounds according to the invention of the general formula I may in each case have the following meanings:

C₁-C₃-, C₁-C₄-, C₁-C₅-, C₁-C₆- and C₁-C₈-alkyl group means unbranched or optionally branched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group.

In the meaning of R¹, R² and R³, the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group are preferred.

According to the invention, preference is given to methyl or ethyl for R⁵, and to hydrogen for R^(6a) and R^(6b).

Alkenyl means unbranched or optionally branched alkenyl radicals. Examples of the meaning of a C₂-C₈-alkenyl group in the context of the invention are the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. When the aromatic in R³ is substituted by a C₂-C₈-alkenyl radical, it is preferably a vinyl group.

Alkynyl means unbranched or optionally branched alkynyl radicals. A C₂-C₈-alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, but preferably an ethynyl or propynyl group.

A C₁-C₃-acyl radical in the context of R^(f) is a formyl, acetyl and an n- or isopropionyl radical. An acetyl radical is preferred for R^(f).

C₁-C₃-Alkoxy is understood to mean a methoxy, ethoxy and an n- or isopropoxy radical. Methoxy and ethoxy are preferred.

Possible examples of C₁-C₆-alkoxyl-C₁-C₆-alkoxy group are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy.

A radical OR^(b) in the context of the invention is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred.

Suitable for a partly or completely fluorinated C₁-C₃-, C₁-C₄- and C₁-C₆-fluoroalkyl group are in particular the trifluoromethyl or pentafluoroethyl group.

A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here.

Possible examples of a mono- or bicyclic C₆-C₁₂-aryl radical in the meaning of R³, or R^(c), R^(d), R^(e), and also K and L, are, for example, a phenyl or naphthyl radical, preferably a phenyl radical.

Examples of a 3-12-membered heteroaryl radical in the meaning of R³, K and L, and also R^(c) and R^(d), are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.

5- to 6-membered C₃-C₁₀-cycloalkyl in the meaning of A, R³, K and L and 3- to 12-membered heterocycloalkyl groups in the meaning of A, R³, K and L are understood to mean both monocyclic and bicyclic groups.

Heteroatoms for 3-12-membered heteroaryls in the meaning of R^(b) and 5-12-membered heteroaryls in the meaning of R^(c) and R^(d) are nitrogen, sulfur or oxygen.

Examples which may be mentioned of monocyclic C₃-C₁₀-cycloalkyl in the meaning of R^(c) and R^(e) are cyclopropane, cyclobutane, cyclopentane and cyclohexane. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.

Examples of monocyclic 3-12-membered or 5-12-membered heterocyclic radicals in the meaning of A, Z, K, R³ or R⁴ are morpholine, tetrahydrofuran, piperidine, pyrrolidine, oxirane, oxetane, aziridine, dioxolane, dioxane, thiophene, furan, pyran, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, thiazole, oxazole, furazan, pyrroline, thiazoline, triazole, tetrazole, using any of the chemically possible isomers in relation to the positions of the heteroatoms.

Examples which may be mentioned of bicyclic 3-12-membered or 5-12-membered heterocycles are quinoline, quinazoline and naphthyridine.

For R⁴, according to the invention, the bicyclic ring systems specified under B and C are preferred.

R¹ and R² which, together with the carbon atom of the chain, can form a carbocyclic ring having a total of 3-7 members are understood to mean carbocycles having 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms. Particular preference is given to cyclopropyl, cyclopentyl and cyclohexyl.

Heterocycles in the sense of R¹ and R², which can be formed together with the carbon atom of the chain, may be cyclic ring compounds having at least one heteroatom, preferably oxygen, nitrogen and sulphur. Particular preference is given to tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl.

The number p for the (CH₂)_(p) radical may be a number 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1 or 2. “Radical” means according to the invention all functional groups which are mentioned under L in connection with (CH₂)_(p).

In the case where the compounds of the general formula I are in the form of salts, this is possible for example in the form of the hydrochloride, sulphate, nitrate, tartrate, citrate, fumarate, succinate or benzoate.

If the compounds according to the invention are in the form of racemic mixtures, they can be fractionated by methods of racemate resolution familiar to the skilled person into the pure optically active forms. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (CHIRALPAK AD®). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid, and to separate the resulting diastereoisomeric esters by fractional crystallization or chromatography and to hydrolyse the separated esters in each case to the optically pure isomers. It is possible to use as optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid.

Compounds of the general formula (I) preferred according to the present invention are those in which A is a hydrogen atom.

Further preferred are compounds in which:

-   Y is a —C≡C-radical, and -   R¹ and R² together with the carbon atom of the chain form a     carbocyclic or heterocyclic 3-6-membered ring and -   R³ is optionally K-substituted C₁-C₈-alkyl, aryl optionally mono- or     polysubstituted identically or differently by L, or 3- to     12-membered heteroaryl -   or -   Y is (CH₂)_(m) and -   R³ is aryl optionally mono- or polysubstituted identically or     differently by L or 3- to 12-membered heteroaryl, and -   R⁴ is mono- or bicyclic aryl disubstituted identically or     differently by L, or one of the B groups specified under R⁴ with     linkage at position 6 or C with linkage at position 5.

In the case that Y is (CH₂)_(m), m is preferably 1.

Irrespective of m, in the case that Y is (CH₂)_(m), R⁴ is a phenyl ring substituted by 2 of the radicals specified under L.

For L, particular preference is given to a cyano radical, a chlorine and/or a trifluoromethyl radical.

In the case that Y is (CH₂)_(m), R⁴, alternatively to the substituted phenyl ring, may also be defined as follows:

For these, the following substituents are preferred:

-   R⁵ is methyl or ethyl, -   R⁶ is hydrogen.

Preference is additionally given to compounds of the general formula (I) in which

-   A is hydrogen, -   p is 0, 1 or 2, -   L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, a partly or fully     fluorinated C₁-C₆-fluoroalkyl, —(CH₂)_(p)CN, (CH₂)_(p)Hal,     (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, —(CH₂)_(p)-heteroaryl,     —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b),     —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d),     —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d),     —(CH₂)_(p)COR^(b), —(CH₂)_(p)S(O)R^(b), —(CH₂)_(p)S(O)₂R^(b),     —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)CO₂R^(b),     —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)OR^(b), (H₂)_(p)CR^(b)(OH)—R^(b)     and -   Z is cyano, halogen, hydroxyl, nitro, —C(O)R^(b), CO₂R^(b), —R^(b),     —SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —NR^(c)R^(d), —NR^(e)COR^(b),     —NR^(e)S(O)R^(b), —NR^(e)S(O)₂R^(b),     -   NR^(e)CONR^(c)R^(d), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),         —CR^(b)(OH)—R^(b) or a C₃-C₁₀-cycloalkyl or heterocycloalkyl         optionally mono- or polysubstituted identically or differently         by M.

Preference is additionally given to compounds of the general formula (I) in which

-   A is hydrogen and -   R¹ and R² together with the carbon atom of the chain form a     cyclopropyl, cyclopentyl or cyclohexyl ring.

Particular preference is given in this context in turn to a tetrahydropyranyl ring, a piperidinyl ring or a tetrahydrothiopyranyl ring.

The compounds mentioned below, and the use thereof, are preferred according to the invention:

    No. Racemic or enantiomer     R3   1   2   3 rac + −

  4   5   6 rac + −

  7   8   9 rac + −

 10  11  12 rac + −

 13  14  15 rac + −

 16  17  18 rac + −

 19  20  21 rac + −

 22  23  24 rac + −

 25  26  27 rac + −

 28  29  30 rac + −

 31  32  33 rac + −

 34  35  36 rac + −

 37  38  39 rac + −

 40  41  42 rac + −

 43  44  45 rac + −

 46  47  48 rac + −

 49  50  51 rac + −

 52  53  54 rac + −

 55  56  57 rac + −

 58  59  60 rac + −

 61  62  63 rac + −

 64  65  66 rac + −

 67  68  69 rac + −

 70  71  72 rac + −

 73  74  75 rac + −

 76  77  78 rac + −

 79  80  81 rac + −

 82  83  84 rac + −

 85  86  87 rac + −

 88  89  90 rac + −

 91  92  93 rac + −

 94  95  96 rac + −

 97  98  99 rac + −

 100  101  102 rac + −

 103  104  105 rac + −

 106  107  108 rac + −

 109  110  111 rac + −

 112  113  114 rac + −

 115  116  117 rac + −

 118  119  120 rac + −

 121  122  123 rac + −

 124  125  126 rac + −

 127  128  129 rac + −

 130  131  132 rac + −

 133  134  135 rac + −

 136  137  138 rac + −

 139  140  141 rac + −

 142  143  144 rac + −

 145  146  147 rac + −

 148  149  150 rac + −

 151  152  153 rac + −

 154  155  156 rac + −

 157  158  159 rac + −

 160  161  162 rac + −

 163  164  165 rac + −

 166  167  168 rac + −

 169  170  171 rac + −

 172  173  174 rac + −

 175  176  177 rac + −

 178  179  180 rac + −

 181  182  183 rac + −

 184  185  186 rac + −

 187  188  189 rac + −

 190  191  192 rac + −

 193  194  195 rac + −

 196  197  198 rac + −

 199  200  201 rac + −

 202  203  204 rac + −

 205  206  207 rac + −

 208  209  210 rac + −

 211  212  213 rac + −

 214  215  216 rac + −

 217  218  219 rac + −

 220  221  222 rac + −

 223  224  225 rac + −

 226  227  228 rac + −

 229  230  231 rac + −

 232  233  234 rac + −

 235  236  237 rac + −

 238  239  240 rac + −

 241  242  243 rac + −

 244  245  246 rac + −

 247  248  249 rac + −

 250  251  252 rac + −

 253  254  255 rac + −

 256  257  258 rac + −

 259  260  261 rac + −

    No. Racemic or enantiomer     R3  262  263  264 rac + −

 265  266  267 rac + −

 268  269  270 rac + −

 271  272  273 rac + −

 274  275  276 rac + −

 277  278  279 rac + −

 280  281  282 rac + −

 283  284  285 rac + −

 286  287  288 rac + −

 289  290  291 rac + −

 292  293  294 rac + −

 295  296  297 rac + −

 298  299  300 rac + −

 301  302  303 rac + −

 304  305  306 rac + −

 307  308  309 rac + −

 310  311  312 rac + −

 313  314  315 rac + −

 316  317  318 rac + −

 319  320  321 rac + −

 322  323  324 rac + −

 325  326  327 rac + −

 328  329  330 rac + −

 331  332  333 rac + −

 334  335  336 rac + −

 337  338  339 rac + −

 340  341  342 rac + −

 343  344  345 rac + −

 346  347  348 rac + −

 349  350  351 rac + −

 352  353  354 rac + −

 355  356  357 rac + −

 358  359  360 rac + −

 361  362  363 rac + −

 364  365  366 rac + −

 367  368  369 rac + −

 370  371  372 rac + −

 373  374  375 rac + −

 376  377  378 rac + −

 379  380  381 rac + −

 382  383  384 rac + −

 385  386  387 rac + −

 388  389  390 rac + −

 391  392  393 rac + −

 394  395  396 rac + −

 397  398  399 rac + −

 400  401  402 rac + −

 403  404  405 rac + −

 406  407  408 rac + −

 409  410  411 rac + −

 412  413  414 rac + −

 415  416  417 rac + −

 418  419  420 rac + −

 421  422  423 rac + −

 424  425  426 rac + −

 427  428  429 rac + −

 430  431  432 rac + −

 433  434  435 rac + −

 436  437  438 rac + −

 439  440  441 rac + −

 442  443  444 rac + −

 445  446  447 rac + −

 448  449  450 rac + −

 451  452  453 rac + −

 454  455  456 rac + −

 457  458  459 rac + −

 460  461  462 rac + −

 463  464  465 rac + −

 466  467  468 rac + −

 469  470  471 rac + −

 472  473  474 rac + −

 475  476  477 rac + −

 478  479  480 rac + −

 481  482  483 rac + −

 484  485  486 rac + −

 487  488  489 rac + −

 490  491  492 rac + −

 493  494  495 rac + −

 496  497  498 rac + −

 499  500  501 rac + −

 502  503  504 rac + −

 505  506  507 rac + −

 508  509  510 rac + −

 511  512  513 rac + −

 514  515  516 rac + −

 517  518  519 rac + −

 520  521  522 rac + −

 523  524  525 rac + −

 526  527  528 rac + −

 529  530  531 rac + −

 532  533  534 rac + −

 535  536  537 rac + −

 538  539  540 rac + −

 541  542  543 rac + −

 544  545  546 rac + −

 547  548  549 rac + −

 550  551  552 rac + −

 553  554  555 rac + −

 556  557  558 rac + −

 559  560  561 rac + −

 562  563  564 rac + −

 565  566  567 rac + −

 568  569  570 rac + −

 571  572  573 rac + −

 574  575  576 rac + −

 577  578  579 rac + −

 580  581  582 rac + −

 583  584  585 rac + −

 586  587  588 rac + −

 589  590  591 rac + −

 592  593  594 rac + −

 595  596  597 rac + −

 598  599  600 rac + −

 601  602  603 rac + −

 604  605  606 rac + −

 607  608  609 rac + −

 610  611  612 rac + −

 613  614  615 rac + −

 616  617  618 rac + −

 619  620  621 rac + −

 622  623  624 rac + −

 625  626  627 rac + −

 628  629  630 rac + −

 631  632  633 rac + −

 634  635  636 rac + −

 637  638  639 rac + −

 640  641  642 rac + −

 643  644  645 rac + −

 646  647  648 rac + −

 649  650  651 rac + −

 652  653  654 rac + −

 655  656  657 rac + −

 658  659  660 rac + −

 661  662  663 rac + −

 664  665  666 rac + −

 667  668  669 rac + −

 670  671  672 rac + −

 673  674  675 rac + −

 676  677  678 rac + −

 679  680  681 rac + −

 682  683  684 rac + −

 685  686  687 rac + −

 688  689  690 rac + −

 691  692  693 rac + −

 694  695  696 rac + −

 697  698  699 rac + −

 700  701  702 rac + −

 703  704  705 rac + −

 706  707  708 rac + −

 709  710  711 rac + −

 712  713  714 rac + −

 715  716  717 rac + −

 718  719  720 rac + −

 721  722  723 rac + −

 724  725  726 rac + −

 727  728  729 rac + −

 730  731  732 rac + −

 733  734  735 rac + −

 736  737  738 rac + −

 739  740  741 rac + −

 742  743  744 rac + −

 745  746  747 rac + −

 748  749  750 rac + −

 751  752  753 rac + −

 754  755  756 rac + −

 757  758  759 rac + −

 760  761  762 rac + −

 763  764  765 rac + −

 766  767  768 rac + −

 769  770  771 rac + −

 772  773  774 rac + −

 775  776  777 rac + −

 778  779  780 rac + −

 781  782  783 rac + −

 784  785  786 rac + −

 787  788  789 rac + −

 790  791  792 rac + −

 793  794  795 rac + −

 796  797  798 rac + −

 799  800  801 rac + −

 802  803  804 rac + −

 805  806  807 rac + −

 808  809  810 rac + −

 811  812  813 rac + −

 814  815  816 rac + −

 817  818  819 rac + −

 820  821  822 rac + −

 823  824  825 rac + −

 826  827  828 rac + −

 829  830  831 rac + −

 832  833  834 rac + −

 835  836  837 rac + −

 838  839  840 rac + −

 841  842  843 rac + −

 844  845  846 rac + −

 847  848  849 rac + −

 850  851  852 rac + −

 853  854  855 rac + −

 856  857  858 rac + −

 859  860  861 rac + −

 862  863  864 rac + −

 865  866  867 rac + −

 868  869  870 rac + −

 871  872  873 rac + −

 874  875  876 rac + −

 877  878  879 rac + −

 880  881  882 rac + −

 883  884  885 rac + −

 886  887  888 rac + −

 889  890  891 rac + −

 892  893  894 rac + −

 895  896  897 rac + −

 898  899  900 rac + −

 901  902  903 rac + −

 904  905  906 rac + −

 907  908  909 rac + −

 910  911  912 rac + −

 913  914  915 rac + −

 916  917  918 rac + −

 919  920  921 rac + −

 922  923  924 rac + −

 925  926  927 rac + −

 928  929  930 rac + −

 931  932  933 rac + −

 934  935  936 rac + −

 937  938  939 rac + −

 940  941  942 rac + −

 943  944  945 rac + −

 946  947  948 rac + −

 949  950  951 rac + −

 952  953  954 rac + −

 955  956  957 rac + −

 958  959  960 rac + −

 961  962  963 rac + −

 964  965  966 rac + −

 967  968  969 rac + −

 970  971  972 rac + −

 973  974  975 rac + −

 976  977  978 rac + −

 979  980  981 rac + −

 982  983  984 rac + −

 985  986  987 rac + −

 988  989  990 rac + −

 991  992  993 rac + −

 994  995  996 rac + −

 997  998  999 rac + −

1000 1001 1002 rac + −

1003 1004 1005 rac + −

1006 1007 1008 rac + −

1009 1010 1011 rac + −

1012 1013 1014 rac + −

1015 1016 1017 rac + −

1018 1019 1020 rac + −

1021 1022 1023 rac + −

1024 1025 1026 rac + −

1027 1028 1029 rac + −

1030 1031 1032 rac + −

1033 1034 1035 rac + −

1036 1037 1038 rac + −

1039 1040 1041 rac + −

1042 1043 1044 rac + −

    No. Racemic or enantiomer     R3 1045 1046 1047 rac + −

1048 1049 1050 rac + −

1051 1052 1053 rac + −

1054 1055 1056 rac + −

1057 1058 1059 rac + −

1060 1061 1062 rac + −

1063 1064 1065 rac + −

1066 1067 1068 rac + −

1069 1070 1071 rac + −

1072 1073 1074 rac + −

1075 1076 1077 rac + −

1078 1079 1080 rac + −

1081 1082 1083 rac + −

1084 1085 1086 rac + −

1087 1088 1089 rac + −

1090 1091 1092 rac + −

1093 1094 1095 rac + −

1096 1097 1098 rac + −

1099 1100 1101 rac + −

1102 1103 1104 rac + −

1105 1106 1107 rac + −

1108 1109 1110 rac + −

1111 1112 1113 rac + −

1114 1115 1116 rac + −

1117 1118 1119 rac + −

1120 1121 1122 rac + −

1123 1124 1125 rac + −

1126 1127 1128 rac + −

1129 1130 1131 rac + −

1132 1133 1134 rac + −

1135 1136 1137 rac + −

1138 1139 1140 rac + −

1141 1142 1143 rac + −

1144 1145 1146 rac + −

1147 1148 1149 rac + −

1150 1151 1152 rac + −

1153 1154 1155 rac + −

1156 1157 1158 rac + −

1159 1160 1161 rac + −

1162 1163 1164 rac + −

1165 1166 1167 rac + −

1168 1169 1170 rac + −

1171 1172 1173 rac + −

1174 1175 1176 rac + −

1177 1178 1179 rac + −

1180 1181 1182 rac + −

1183 1184 1185 rac + −

1186 1187 1188 rac + −

1189 1190 1191 rac + −

1192 1193 1194 rac + −

1195 1196 1197 rac + −

1198 1199 1200 rac + −

1201 1202 1203 rac + −

1204 1205 1206 rac + −

1207 1208 1209 rac + −

1210 1211 1212 rac + −

1213 1214 1215 rac + −

1216 1217 1218 rac + −

1219 1220 1221 rac + −

1222 1223 1224 rac + −

1225 1226 1227 rac + −

1228 1229 1230 rac + −

1231 1232 1233 rac + −

1234 1235 1236 rac + −

1237 1238 1239 rac + −

1240 1241 1242 rac + −

1243 1244 1245 rac + −

1246 1247 1248 rac + −

1249 1250 1251 rac + −

1252 1253 1254 rac + −

1255 1256 1257 rac + −

1258 1259 1260 rac + −

1261 1262 1263 rac + −

1264 1265 1266 rac + −

1267 1268 1269 rac + −

1270 1271 1272 rac + −

1273 1274 1275 rac + −

1276 1277 1278 rac + −

1279 1280 1281 rac + −

1282 1283 1284 rac + −

1285 1286 1287 rac + −

1288 1289 1290 rac + −

1291 1292 1293 rac + −

1294 1295 1296 rac + −

1297 1298 1299 rac + −

1300 1301 1302 rac + −

1303 1304 1305 rac + −

    No. Racemic or enantiomer     R3 1306 1307 1308 rac + −

1309 1310 1311 rac + −

1312 1313 1314 rac + −

1315 1316 1317 rac + −

1318 1319 1320 rac + −

1321 1322 1323 rac + −

1324 1325 1326 rac + −

1327 1328 1329 rac + −

1330 1331 1332 rac + −

1333 1334 1335 rac + −

1336 1337 1338 rac + −

1339 1340 1341 rac + −

1342 1343 1344 rac + −

1345 1346 1347 rac + −

1348 1349 1350 rac + −

1351 1352 1353 rac + −

1354 1355 1356 rac + −

1357 1358 1359 rac + −

1360 1361 1362 rac + −

1363 1364 1365 rac + −

1366 1367 1368 rac + −

1369 1370 1371 rac + −

1372 1373 1374 rac + −

1375 1376 1377 rac + −

1378 1379 1380 rac + −

1381 1382 1383 rac + −

1384 1385 1386 rac + −

1387 1388 1389 rac + −

1390 1391 1392 rac + −

1393 1394 1395 rac + −

1396 1397 1398 rac + −

1399 1400 1401 rac + −

1402 1403 1404 rac + −

1405 1406 1407 rac + −

1408 1409 1410 rac + −

1411 1412 1413 rac + −

1414 1415 1416 rac + −

1417 1418 1419 rac + −

1420 1421 1422 rac + −

1423 1424 1425 rac + −

1426 1427 1428 rac + −

1429 1430 1431 rac + −

1432 1433 1434 rac + −

1435 1436 1437 rac + −

1438 1439 1440 rac + −

1441 1442 1443 rac + −

1444 1445 1446 rac + −

1447 1448 1449 rac + −

1450 1451 1452 rac + −

1453 1454 1455 rac + −

1456 1457 1458 rac + −

1459 1460 1461 rac + −

1462 1463 1464 rac + −

1465 1466 1467 rac + −

1468 1469 1470 rac + −

1471 1472 1473 rac + −

1474 1475 1476 rac + −

1477 1478 1479 rac + −

1480 1481 1482 rac + −

1483 1484 1485 rac + −

1486 1487 1488 rac + −

1489 1490 1491 rac + −

1492 1493 1494 rac + −

1495 1496 1497 rac + −

1498 1499 1500 rac + −

1501 1502 1503 rac + −

1504 1505 1506 rac + −

1507 1508 1509 rac + −

1510 1511 1512 rac + −

1513 1514 1515 rac + −

1516 1517 1518 rac + −

1519 1520 1521 rac + −

1522 1523 1524 rac + −

1525 1526 1527 rac + −

1528 1529 1530 rac + −

1531 1532 1533 rac + −

1534 1535 1536 rac + −

1537 1538 1539 rac + −

1540 1541 1542 rac + −

1543 1544 1545 rac + −

1546 1547 1548 rac + −

1549 1550 1551 rac + −

1552 1553 1554 rac + −

1555 1556 1557 rac + −

1558 1559 1560 rac + −

1561 1562 1563 rac + −

1564 1565 1566 rac + −

    No. Racemic or enantiomer     R3 1567 1568 1569 rac + −

1570 1571 1572 rac + −

1573 1574 1575 rac + −

1576 1577 1578 rac + −

1579 1580 1581 rac + −

1582 1583 1584 rac + −

1585 1586 1587 rac + −

1588 1589 1590 rac + −

1591 1592 1593 rac + −

1594 1595 1596 rac + −

1597 1598 1599 rac + −

1600 1601 1602 rac + −

1603 1604 1605 rac + −

1606 1607 1608 rac + −

1609 1610 1611 rac + −

1612 1613 1614 rac + −

1615 1616 1617 rac + −

1618 1619 1620 rac + −

1621 1622 1623 rac + −

1624 1625 1626 rac + −

1627 1628 1629 rac + −

1630 1631 1632 rac + −

1633 1634 1635 rac + −

1636 1637 1638 rac + −

1639 1640 1641 rac + −

1642 1643 1644 rac + −

1645 1646 1647 rac + −

1648 1649 1650 rac + −

1651 1652 1653 rac + −

1654 1655 1656 rac + −

1657 1658 1659 rac + −

1660 1661 1662 rac + −

1663 1664 1665 rac + −

1666 1667 1668 rac + −

1669 1670 1671 rac + −

1672 1673 1674 rac + −

1675 1676 1677 rac + −

1678 1679 1680 rac + −

1681 1682 1683 rac + −

1684 1685 1686 rac + −

1687 1688 1689 rac + −

1690 1691 1692 rac + −

1693 1694 1695 rac + −

1696 1697 1698 rac + −

1699 1700 1701 rac + −

1702 1703 1704 rac + −

1705 1706 1707 rac + −

1708 1709 1710 rac + −

1711 1712 1713 rac + −

1714 1715 1716 rac + −

1717 1718 1719 rac + −

1720 1721 1722 rac + −

1723 1724 1725 rac + −

1726 1727 1728 rac + −

1729 1730 1731 rac + −

1732 1733 1734 rac + −

1735 1736 1737 rac + −

1738 1739 1740 rac + −

1741 1742 1743 rac + −

1744 1745 1746 rac + −

1747 1748 1749 rac + −

1750 1751 1752 rac + −

1753 1754 1755 rac + −

1756 1757 1758 rac + −

1759 1760 1761 rac + −

1762 1763 1764 rac + −

1765 1766 1767 rac + −

1768 1769 1770 rac + −

1771 1772 1773 rac + −

1774 1775 1776 rac + −

1777 1778 1779 rac + −

1780 1781 1782 rac + −

1783 1784 1785 rac + −

1786 1787 1788 rac + −

1789 1790 1791 rac + −

1792 1793 1794 rac + −

1795 1796 1797 rac + −

1798 1799 1800 rac + −

1801 1802 1803 rac + −

1804 1805 1806 rac + −

1807 1808 1809 rac + −

1810 1811 1812 rac + −

1813 1814 1815 rac + −

1816 1817 1818 rac + −

1819 1820 1821 rac + −

1822 1823 1824 rac + −

1825 1826 1827 rac + −

    No. Racemic or enantiomer     R3 1828 1829 1830 rac + −

1831 1832 1833 rac + −

1834 1835 1836 rac + −

1837 1838 1839 rac + −

1840 1841 1842 rac + −

1843 1844 1845 rac + −

1846 1847 1848 rac + −

1849 1850 1851 rac + −

1852 1853 1854 rac + −

1855 1856 1857 rac + −

1858 1859 1860 rac + −

1861 1862 1863 rac + −

1864 1865 1866 rac + −

1867 1868 1869 rac + −

1870 1871 1872 rac + −

1873 1874 1875 rac + −

1876 1877 1878 rac + −

1879 1880 1881 rac + −

1882 1883 1884 rac + −

1885 1886 1887 rac + −

1888 1889 1890 rac + −

1891 1892 1893 rac + −

1894 1895 1896 rac + −

1897 1898 1899 rac + −

1900 1901 1902 rac + −

1903 1904 1905 rac + −

1906 1907 1908 rac + −

1909 1910 1911 rac + −

1912 1913 1914 rac + −

1915 1916 1917 rac + −

1918 1919 1920 rac + −

1921 1922 1923 rac + −

1924 1925 1926 rac + −

1927 1928 1929 rac + −

1930 1931 1932 rac + −

1933 1934 1935 rac + −

1936 1937 1938 rac + −

1939 1940 1941 rac + −

1942 1943 1944 rac + −

1945 1946 1947 rac + −

1948 1949 1950 rac + −

1951 1952 1953 rac + −

1954 1955 1956 rac + −

1957 1958 1959 rac + −

1960 1961 1962 rac + −

1963 1964 1965 rac + −

1966 1967 1968 rac + −

1969 1970 1971 rac + −

1972 1973 1974 rac + −

1975 1976 1977 rac + −

1978 1979 1980 rac + −

1981 1982 1983 rac + −

1984 1985 1986 rac + −

1987 1988 1989 rac + −

1990 1991 1992 rac + −

1993 1994 1995 rac + −

1996 1997 1998 rac + −

1999 2000 2001 rac + −

2002 2003 2004 rac + −

2005 2006 2007 rac + −

2008 2009 2010 rac + −

2011 2012 2013 rac + −

2014 2015 2016 rac + −

2017 2018 2019 rac + −

2020 2021 2022 rac + −

2023 2024 2025 rac + −

2026 2027 2028 rac + −

2029 2030 2031 rac + −

2032 2033 2034 rac + −

2035 2036 2037 rac + −

2038 2039 2040 rac + −

2041 2042 2043 rac + −

2044 2045 2046 rac + −

2047 2048 2049 rac + −

2050 2051 2052 rac + −

2053 2054 2055 rac + −

2056 2057 2058 rac + −

2059 2060 2061 rac + −

2062 2063 2064 rac + −

2065 2066 2067 rac + −

2068 2069 2070 rac + −

2071 2072 2073 rac + −

2074 2075 2076 rac + −

2077 2078 2079 rac + −

2080 2081 2082 rac + −

2083 2084 2085 rac + −

2086 2087 2088 rac + −

    No. Racemic or enantiomer     R3 2089 2090 2091 rac + −

2092 2093 2094 rac + −

2095 2096 2097 rac + −

2098 2099 2100 rac + −

2101 2102 2103 rac + −

2104 2105 2106 rac + −

2107 2108 2109 rac + −

2110 2111 2112 rac + −

2113 2114 2115 rac + −

2116 2117 2118 rac + −

2119 2120 2121 rac + −

2122 2123 2124 rac + −

2125 2126 2127 rac + −

2128 2129 2130 rac + −

2131 2132 2133 rac + −

2134 2135 2136 rac + −

2137 2138 2139 rac + −

2140 2141 2142 rac + −

2143 2144 2145 rac + −

2146 2147 2148 rac + −

2149 2150 2151 rac + −

2152 2153 2154 rac + −

2155 2156 2157 rac + −

2158 2159 2160 rac + −

2161 2162 2163 rac + −

2164 2165 2166 rac + −

2167 2168 2169 rac + −

2170 2171 2172 rac + −

2173 2174 2175 rac + −

2176 2177 2178 rac + −

2179 2180 2181 rac + −

2182 2183 2184 rac + −

2185 2186 2187 rac + −

2188 2189 2190 rac + −

2191 2192 2193 rac + −

2194 2195 2196 rac + −

2197 2198 2199 rac + −

2200 2201 2202 rac + −

2203 2204 2205 rac + −

2206 2207 2208 rac + −

2209 2210 2211 rac + −

2212 2213 2214 rac + −

2215 2216 2217 rac + −

2218 2219 2220 rac + −

2221 2222 2223 rac + −

2224 2225 2226 rac + −

2227 2228 2229 rac + −

2230 2231 2232 rac + −

2233 2234 2235 rac + −

2236 2237 2238 rac + −

2239 2240 2241 rac + −

2242 2243 2244 rac + −

2245 2246 2247 rac + −

2248 2249 2250 rac + −

2251 2252 2253 rac + −

2254 2255 2256 rac + −

2257 2258 2259 rac + −

2260 2261 2262 rac + −

2263 2264 2265 rac + −

2266 2267 2268 rac + −

2269 2270 2271 rac + −

2272 2273 2274 rac + −

2275 2276 2277 rac + −

2278 2279 2280 rac + −

2281 2282 2283 rac + −

2284 2285 2286 rac + −

2287 2288 2289 rac + −

2290 2291 2292 rac + −

2293 2294 2295 rac + −

2296 2297 2298 rac + −

2299 2300 2301 rac + −

2302 2303 2304 rac + −

2305 2306 2307 rac + −

2308 2309 2310 rac + −

2311 2312 2313 rac + −

2314 2315 2316 rac + −

2317 2318 2319 rac + −

2320 2321 2322 rac + −

2323 2324 2325 rac + −

2326 2327 2328 rac + −

2329 2330 2331 rac + −

2332 2333 2334 rac + −

2335 2336 2337 rac + −

2338 2339 2340 rac + −

2341 2342 2343 rac + −

2344 2345 2346 rac + −

2347 2348 2349 rac + −

    No. Racemic or enantiomer     R3 2350 2351 2352 rac + −

2353 2354 2355 rac + −

2356 2357 2358 rac + −

2359 2360 2361 rac + −

2362 2363 2364 rac + −

2365 2366 2367 rac + −

2368 2369 2370 rac + −

2371 2372 2373 rac + −

2374 2375 2376 rac + −

2377 2378 2379 rac + −

2380 2381 2382 rac + −

2383 2384 2385 rac + −

2386 2387 2388 rac + −

2389 2390 2391 rac + −

2392 2393 2394 rac + −

2395 2396 2397 rac + −

2398 2399 2400 rac + −

2401 2402 2403 rac + −

2404 2405 2406 rac + −

2407 2408 2409 rac + −

2410 2411 2412 rac + −

2413 2414 2415 rac + −

2416 2417 2418 rac + −

2419 2420 2421 rac + −

2422 2423 2424 rac + −

2425 2426 2427 rac + −

2428 2429 2430 rac + −

2431 2432 2433 rac + −

2434 2435 2436 rac + −

2437 2438 2439 rac + −

2440 2441 2442 rac + −

2443 2444 2445 rac + −

2446 2447 2448 rac + −

2449 2450 2451 rac + −

2452 2453 2454 rac + −

2455 2456 2457 rac + −

2458 2459 2460 rac + −

2461 2462 2463 rac + −

2464 2465 2466 rac + −

2467 2468 2469 rac + −

2470 2471 2472 rac + −

2473 2474 2475 rac + −

2476 2477 2478 rac + −

2479 2480 2481 rac + −

2482 2483 2484 rac + −

2485 2486 2487 rac + −

2488 2489 2490 rac + −

2491 2492 2493 rac + −

2494 2495 2496 rac + −

2497 2498 2499 rac + −

2500 2501 2502 rac + −

2503 2504 2505 rac + −

2506 2507 2508 rac + −

2509 2510 2511 rac + −

2512 2513 2514 rac + −

2515 2516 2517 rac + −

2518 2519 2520 rac + −

2521 2522 2523 rac + −

2524 2525 2526 rac + −

2527 2528 2529 rac + −

2530 2531 2532 rac + −

2533 2534 2535 rac + −

2536 2537 2538 rac + −

2539 2540 2541 rac + −

2542 2543 2544 rac + −

2545 2546 2547 rac + −

2548 2549 2550 rac + −

2551 2552 2553 rac + −

2554 2555 2556 rac + −

2557 2558 2559 rac + −

2560 2561 2562 rac + −

2563 2564 2565 rac + −

2566 2567 2568 rac + −

2569 2570 2571 rac + −

2572 2573 2574 rac + −

2575 2576 2577 rac + −

2578 2579 2580 rac + −

2581 2582 2583 rac + −

2584 2585 2586 rac + −

2587 2588 2589 rac + −

2590 2591 2592 rac + −

2593 2594 2595 rac + −

2596 2597 2598 rac + −

2599 2600 2601 rac + −

2602 2603 2604 rac + −

2605 2606 2607 rac + −

2608 2609 2610 rac + −

    No. Racemic or enantiomer     R3 2611 2612 2613 rac + −

2614 2615 2616 rac + −

2617 2618 2619 rac + −

2620 2621 2622 rac + −

2623 2624 2625 rac + −

2626 2627 2628 rac + −

2629 2630 2631 rac + −

2632 2633 2634 rac + −

2635 2636 2637 rac + −

2638 2639 2640 rac + −

2641 2642 2643 rac + −

2644 2645 2646 rac + −

2647 2648 2649 rac + −

2650 2651 2652 rac + −

2653 2654 2655 rac + −

2656 2657 2658 rac + −

2659 2660 2661 rac + −

2662 2663 2664 rac + −

2665 2666 2667 rac + −

2668 2669 2670 rac + −

2671 2672 2673 rac + −

2674 2675 2676 rac + −

2677 2678 2679 rac + −

2680 2681 2682 rac + −

2683 2684 2685 rac + −

2686 2687 2688 rac + −

2689 2690 2691 rac + −

2692 2693 2694 rac + −

2695 2696 2697 rac + −

2698 2699 2700 rac + −

2701 2702 2703 rac + −

2704 2705 2706 rac + −

2707 2708 2709 rac + −

2710 2711 2712 rac + −

2713 2714 2715 rac + −

2716 2717 2718 rac + −

2719 2720 2721 rac + −

2722 2723 2724 rac + −

2725 2726 2727 rac + −

2728 2729 2730 rac + −

2731 2732 2733 rac + −

2734 2735 2736 rac + −

2737 2738 2739 rac + −

2740 2741 2742 rac + −

2743 2744 2745 rac + −

2746 2747 2748 rac + −

2749 2750 2751 rac + −

2752 2753 2754 rac + −

2755 2756 2757 rac + −

2758 2759 2760 rac + −

2761 2762 2763 rac + −

2764 2765 2766 rac + −

2767 2768 2769 rac + −

2770 2771 2772 rac + −

2773 2774 2775 rac + −

2776 2777 2778 rac + −

2779 2780 2781 rac + −

2782 2783 2784 rac + −

2785 2786 2787 rac + −

2788 2789 2790 rac + −

2791 2792 2793 rac + −

2794 2795 2796 rac + −

2797 2798 2799 rac + −

2800 2801 2802 rac + −

2803 2804 2805 rac + −

2806 2807 2808 rac + −

2809 2810 2811 rac + −

2812 2813 2814 rac + −

2815 2816 2817 rac + −

2818 2819 2820 rac + −

2821 2822 2823 rac + −

2824 2825 2826 rac + −

2827 2828 2829 rac + −

2830 2831 2832 rac + −

2833 2834 2835 rac + −

2836 2837 2838 rac + −

2839 2840 2841 rac + −

2842 2843 2844 rac + −

2845 2846 2847 rac + −

2848 2849 2850 rac + −

2851 2852 2853 rac + −

2854 2855 2856 rac + −

2857 2858 2859 rac + −

2860 2861 2862 rac + −

2863 2864 2865 rac + −

2866 2867 2868 rac + −

2869 2870 2871 rac + −

    No. Racemic or enantiomer     R3 2872 2873 2874 rac + −

2875 2876 2877 rac + −

2878 2879 2880 rac + −

2881 2882 2883 rac + −

2884 2885 2886 rac + −

2887 2888 2889 rac + −

2890 2891 2892 rac + −

2893 2894 2895 rac + −

2896 2897 2898 rac + −

2899 2900 2901 rac + −

2902 2903 2904 rac + −

2905 2906 2907 rac + −

2908 2909 2910 rac + −

2911 2912 2913 rac + −

2914 2915 2916 rac + −

2917 2918 2919 rac + −

2920 2921 2922 rac + −

2923 2924 2925 rac + −

2926 2927 2928 rac + −

2929 2930 2931 rac + −

2932 2933 2934 rac + −

2935 2936 2937 rac + −

2938 2939 2940 rac + −

2941 2942 2943 rac + −

2944 2945 2946 rac + −

2947 2948 2949 rac + −

2950 2951 2952 rac + −

2953 2954 2955 rac + −

2956 2957 2958 rac + −

2959 2960 2961 rac + −

2962 2963 2964 rac + −

2965 2966 2967 rac + −

2968 2969 2970 rac + −

2971 2972 2973 rac + −

2974 2975 2976 rac + −

2977 2978 2979 rac + −

2980 2981 2982 rac + −

2983 2984 2985 rac + −

2986 2987 2988 rac + −

2989 2990 2991 rac + −

2992 2993 2994 rac + −

2995 2996 2997 rac + −

2998 2999 3000 rac + −

3001 3002 3003 rac + −

3004 3005 3006 rac + −

3007 3008 3009 rac + −

3010 3011 3012 rac + −

3013 3014 3015 rac + −

3016 3017 3018 rac + −

3019 3020 3021 rac + −

3022 3023 3024 rac + −

3025 3026 3027 rac + −

3028 3029 3030 rac + −

3031 3032 3033 rac + −

3034 3035 3036 rac + −

3037 3038 3039 rac + −

3040 3041 3042 rac + −

3043 3044 3045 rac + −

3046 3047 3048 rac + −

3049 3050 3051 rac + −

3052 3053 3054 rac + −

3055 3056 3057 rac + −

3058 3059 3060 rac + −

3061 3062 3063 rac + −

3064 3065 3066 rac + −

3067 3068 3069 rac + −

3070 3071 3072 rac + −

3073 3074 3075 rac + −

3076 3077 3078 rac + −

3079 3080 3081 rac + −

3082 3083 3084 rac + −

3085 3086 3087 rac + −

3088 3089 3090 rac + −

3091 3092 3093 rac + −

3094 3095 3096 rac + −

3097 3098 3099 rac + −

3100 3101 3102 rac + −

3103 3104 3105 rac + −

3106 3107 3108 rac + −

3109 3110 3111 rac + −

3112 3113 3114 rac + −

3115 3116 3117 rac + −

3118 3119 3120 rac + −

3121 3122 3123 rac + −

3124 3125 3126 rac + −

3127 3128 3129 rac + −

3130 3131 3132 rac + −

    No. Racemic or enantiomer     R3 3133 3134 3135 rac + −

3136 3137 3138 rac + −

3139 3140 3141 rac + −

3142 3143 3144 rac + −

3145 3146 3147 rac + −

3148 3149 3150 rac + −

3151 3152 3153 rac + −

3154 3155 3156 rac + −

3157 3158 3159 rac + −

3160 3161 3162 rac + −

3163 3164 3165 rac + −

3166 3167 3168 rac + −

3169 3170 3171 rac + −

3172 3173 3174 rac + −

3175 3176 3177 rac + −

3178 3179 3180 rac + −

3181 3182 3183 rac + −

3184 3185 3186 rac + −

3187 3188 3189 rac + −

3190 3191 3192 rac + −

3193 3194 3195 rac + −

3196 3197 3198 rac + −

3199 3200 3201 rac + −

3202 3203 3204 rac + −

3205 3206 3207 rac + −

3208 3209 3210 rac + −

3211 3212 3213 rac + −

3214 3215 3216 rac + −

3217 3218 3219 rac + −

3220 3221 3222 rac + −

3223 3224 3225 rac + −

3226 3227 3228 rac + −

3229 3230 3231 rac + −

3232 3233 3234 rac + −

3235 3236 3237 rac + −

3238 3239 3240 rac + −

3241 3242 3243 rac + −

3244 3245 3246 rac + −

3247 3248 3249 rac + −

3250 3251 3252 rac + −

3253 3254 3255 rac + −

3256 3257 3258 rac + −

3259 3260 3261 rac + −

3262 3263 3264 rac + −

3265 3266 3267 rac + −

3268 3269 3270 rac + −

3271 3272 3273 rac + −

3274 3275 3276 rac + −

3277 3278 3279 rac + −

3280 3281 3282 rac + −

3283 3284 3285 rac + −

3286 3287 3288 rac + −

3289 3290 3291 rac + −

3292 3293 3294 rac + −

3295 3296 3297 rac + −

3298 3299 3300 rac + −

3301 3302 3303 rac + −

3304 3305 3306 rac + −

3307 3308 3309 rac + −

3310 3311 3312 rac + −

3313 3314 3315 rac + −

3316 3317 3318 rac + −

3319 3320 3321 rac + −

3322 3323 3324 rac + −

3325 3326 3327 rac + −

3328 3329 3330 rac + −

3331 3332 3333 rac + −

3334 3335 3336 rac + −

3337 3338 3339 rac + −

3340 3341 3342 rac + −

3343 3344 3345 rac + −

3346 3347 3348 rac + −

3349 3350 3351 rac + −

3352 3353 3354 rac + −

3355 3356 3357 rac + −

3358 3359 3360 rac + −

3361 3362 3363 rac + −

3364 3365 3366 rac + −

3367 3368 3369 rac + −

3370 3371 3372 rac + −

3373 3374 3375 rac + −

3376 3377 3378 rac + −

3379 3380 3381 rac + −

3382 3383 3384 rac + −

3385 3386 3387 rac + −

3388 3389 3390 rac + −

3391 3392 3393 rac + −

    No. Racemic or enantiomer     R3 3394 3395 3396 rac + −

3397 3398 3399 rac + −

3400 3401 3402 rac + −

3403 3404 3405 rac + −

3406 3407 3408 rac + −

3409 3410 3411 rac + −

3412 3413 3414 rac + −

3415 3416 3417 rac + −

3418 3419 3420 rac + −

3421 3422 3423 rac + −

3424 3425 3426 rac + −

3427 3428 3429 rac + −

3430 3431 3432 rac + −

3433 3434 3435 rac + −

3436 3437 3438 rac + −

3439 3440 3441 rac + −

3442 3443 3444 rac + −

3445 3446 3447 rac + −

3448 3449 3450 rac + −

3451 3452 3453 rac + −

3454 3455 3456 rac + −

3457 3458 3459 rac + −

3460 3461 3462 rac + −

3463 3464 3465 rac + −

3466 3467 3468 rac + −

3469 3470 3471 rac + −

3472 3473 3474 rac + −

3475 3476 3477 rac + −

3478 3479 3480 rac + −

3481 3482 3483 rac + −

3484 3485 3486 rac + −

3487 3488 3489 rac + −

3490 3491 3492 rac + −

3493 3494 3495 rac + −

3496 3497 3498 rac + −

3499 3500 3501 rac + −

3502 3503 3504 rac + −

3505 3506 3507 rac + −

3508 3509 3510 rac + −

3511 3512 3513 rac + −

3514 3515 3516 rac + −

3517 3518 3519 rac + −

3520 3521 3522 rac + −

3523 3524 3525 rac + −

3526 3527 3528 rac + −

3529 3530 3531 rac + −

3532 3533 3534 rac + −

3535 3536 3537 rac + −

3538 3539 3540 rac + −

3541 3542 3543 rac + −

3544 3545 3546 rac + −

3547 3548 3549 rac + −

3550 3551 3552 rac + −

3553 3554 3555 rac + −

3556 3557 3558 rac + −

3559 3560 3561 rac + −

3562 3563 3564 rac + −

3565 3566 3567 rac + −

3568 3569 3570 rac + −

3571 3572 3573 rac + −

3574 3575 3576 rac + −

3577 3578 3579 rac + −

3580 3581 3582 rac + −

3583 3584 3585 rac + −

3586 3587 3588 rac + −

3589 3590 3591 rac + −

3592 3593 3594 rac + −

3595 3596 3597 rac + −

3598 3599 3600 rac + −

3601 3602 3603 rac + −

3604 3605 3606 rac + −

3607 3608 3609 rac + −

3610 3611 3612 rac + −

3613 3614 3615 rac + −

3616 3617 3618 rac + −

3619 3620 3621 rac + −

3622 3623 3624 rac + −

3625 3626 3627 rac + −

3628 3629 3630 rac + −

3631 3632 3633 rac + −

3634 3635 3636 rac + −

3637 3638 3639 rac + −

3640 3641 3642 rac + −

3643 3644 3645 rac + −

3646 3647 3648 rac + −

3649 3650 3651 rac + −

3652 3653 3654 rac + −

    No. Racemic or enantiomer     R3 3655 3656 3657 rac + −

3658 3659 3660 rac + −

3661 3662 3663 rac + −

3664 3665 3666 rac + −

3667 3668 3669 rac + −

3670 3671 3672 rac + −

3673 3674 3675 rac + −

3676 3677 3678 rac + −

3679 3680 3681 rac + −

3682 3683 3684 rac + −

3685 3686 3687 rac + −

3688 3689 3690 rac + −

3691 3692 3693 rac + −

3694 3695 3696 rac + −

3697 3698 3699 rac + −

3700 3701 3702 rac + −

3703 3704 3705 rac + −

3706 3707 3708 rac + −

3709 3710 3711 rac + −

3712 3713 3714 rac + −

3715 3716 3717 rac + −

3718 3719 3720 rac + −

3721 3722 3723 rac + −

3724 3725 3726 rac + −

3727 3728 3729 rac + −

3730 3731 3732 rac + −

3733 3734 3735 rac + −

3736 3737 3738 rac + −

3739 3740 3741 rac + −

3742 3743 3744 rac + −

3745 3746 3747 rac + −

3748 3749 3750 rac + −

3751 3752 3753 rac + −

3754 3755 3756 rac + −

3757 3758 3759 rac + −

3760 3761 3762 rac + −

3763 3764 3765 rac + −

3766 3767 3768 rac + −

3769 3770 3771 rac + −

3772 3773 3774 rac + −

3775 3776 3777 rac + −

3778 3779 3780 rac + −

3781 3782 3783 rac + −

3784 3785 3786 rac + −

3787 3788 3789 rac + −

3790 3791 3792 rac + −

3793 3794 3795 rac + −

3796 3797 3798 rac + −

3799 3800 3801 rac + −

3802 3803 3804 rac + −

3805 3806 3807 rac + −

3808 3809 3810 rac + −

3811 3812 3813 rac + −

3814 3815 3816 rac + −

3817 3818 3819 rac + −

3820 3821 3822 rac + −

3823 3824 3825 rac + −

3826 3827 3828 rac + −

3829 3830 3831 rac + −

3832 3833 3834 rac + −

3835 3836 3837 rac + −

3838 3839 3840 rac + −

3841 3842 3843 rac + −

3844 3845 3846 rac + −

3847 3848 3849 rac + −

3850 3851 3852 rac + −

3853 3854 3855 rac + −

3856 3857 3858 rac + −

3859 3860 3861 rac + −

3862 3863 3864 rac + −

3865 3866 3867 rac + −

3868 3869 3870 rac + −

3871 3872 3873 rac + −

3874 3875 3876 rac + −

3877 3878 3879 rac + −

3880 3881 3882 rac + −

3883 3884 3885 rac + −

3886 3887 3888 rac + −

3889 3890 3891 rac + −

3892 3893 3894 rac + −

3895 3896 3897 rac + −

3898 3899 3900 rac + −

3901 3902 3903 rac + −

3904 3905 3906 rac + −

3907 3908 3909 rac + −

3910 3911 3912 rac + −

3913 3914 3915 rac + −

    No. racemic or enantiomer or stereoisomer     structure 3916 3917 3918 rac + −

3919   3920 3921 3922 3923 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

3924 3925 3926 rac + −

3927 3928 3929 rac + −

3930 3931 3932 rac + −

3933 3934 3935 rac + −

3936 3937 3938 rac + −

3939 3940 3941 rac + −

3942 3943 3944 rac + −

3945 3946 3947 rac + −

3948 3949 3950 rac + −

3951 3952 3953 rac + −

3954 3955 3956 rac + −

3957 3958 3959 rac + −

3960 3961 3962 rac + −

3963 3964 3965 rac + −

3966   3967 3968 3969 3970 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

3971 3972 3973 rac + −

3974 3975 3976 rac + −

3977 3978 3979 rac + −

3980 3981 3982 rac + −

3983 3984 3985 rac + −

3986 3987 3988 rac + −

3989 3990 3991 rac + −

3992 3993 3994 rac + −

3995 3996 3997 rac + −

3998   3999 4000 4001 4002 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4003 4004 4005 rac + −

4006 4007 4008 rac + −

4009 4010 4011 rac + −

4012 4013 4014 rac + −

4015 4016 4017 rac + −

4018 4019 4020 rac + −

4021 4022 4023 rac + −

4024 4025 4026 rac + −

4027 4028 4029 rac + −

4030 4031 4032 rac + −

4033 4034 4035 rac + −

4036 4037 4038 rac + −

4039 4040 4041 rac + −

4042 4043 4044 rac + −

4045 4046 4047 rac + −

4048 4049 4050 rac + −

4051 4052 4053 rac + −

4054 4055 4056 rac + −

4057 4058 4059 rac + −

4060 4061 4062 rac + −

4063 4064 4065 rac + −

4066 4067 4068 rac + −

4069 4070 4071 rac + −

4072 4073 4074 rac + −

4075 4076 4077 rac + −

4078 4079 4080 rac + −

4081 4082 4083 rac + −

4084 4085 4086 rac + −

4087 4088 4089 rac + −

4090 4091 4092 rac + −

4093 4094 4095 rac + −

4096 4097 4098 rac + −

4099 4100 4101 rac + −

4102 4103 4104 rac + −

4105 4106 4107 rac + −

4108 4109 4110 rac + −

4111 4112 4113 rac + −

4114 4115 4116 rac + −

4117 4118 4119 rac + −

4120 4121 4122 rac + −

4123 4124 4125 rac + −

4126 4127 4128 rac + −

4129 4130 4131 rac + −

4132 4133 4134 rac + −

4135 4136 4137 rac + −

4138 4139 4140 rac + −

4141 4142 4143 rac + −

4144 4145 4146 rac + −

4147 4148 4149 rac + −

4150 4151 4152 rac + −

4153 4154 4155 rac + −

4156 4157 4158 rac + −

4159 4160 4161 rac + −

4162 4163 4164 rac + −

4165 4166 4167 rac + −

4168 4169 4170 rac + −

4171 4172 4173 rac + −

4174 4175 4176 rac + −

4177 4178 4179 rac + −

4180 4181 4182 rac + −

4183 4184 4185 rac + −

4186 4187 4188 rac + −

4189 4190 4191 rac + −

4192 4193 4194 rac + −

4195 4196 4197 rac + −

4198 4199 4200 rac + −

4201 4202 4203 rac + −

4204 4205 4206 rac + −

4207 4208 4209 rac + −

4210 4211 4212 rac + −

4213 4214 4215 rac + −

4216 4217 4218 rac + −

4219 4220 4221 rac + −

4222 4223 4224 rac + −

4225 4226 4227 rac + −

4228 4229 4230 rac + −

4231 4232 4233 rac + −

4234 4235 4236 rac + −

4237 4238 4239 rac + −

4240 4241 4242 rac + −

4243 4244 4245 rac + −

4246 4247 4248 rac + −

4249 4250 4251 rac + −

4252 4253 4254 rac + −

4255 4256 4257 rac + −

4258 4259 4260 rac + −

4261 4262 4263 rac + −

4264 4265 4266 rac + −

4267 4268 4269 rac + −

4270 4271 4272 rac + −

4273 4274 4275 rac + −

4276 4277 4278 rac + −

4279 4280 4281 rac + −

4282 4283 4284 rac + −

4285   4286 4287 4288 4289 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4290   4291 4292 4293 4294 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4295 4296 4297 rac + −

4298 4299 4300 rac + −

4301   4302 4303 4304 4305 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4306 4307 4308 rac + −

4309 4310 4311 rac + −

4312 4313 4314 rac + −

4315 4316 4317 rac + −

4318 4319 4320 rac + −

4321 4322 4323 rac + −

4324 4325 4326 rac + −

4327 4328 4329 rac + −

4330 4331 4332 rac + −

4333 4334 4335 rac + −

4336 4337 4338 rac + −

4339 4340 4341 rac + −

4342 4343 4344 rac + −

4345 4346 4347 rac + −

4348 4349 4350 rac + −

4351 4352 4353 rac + −

4354 4355 4356 rac + −

4357 4358 4359 rac + −

4360 4361 4362 rac + −

4363 4364 4365 rac + −

4366 4367 4368 rac + −

4369   4370 4371 4372 4373 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4374 4375 4376 rac + −

4377 4378 4379 rac + −

4380 4381 4382 rac + −

4383 4384 4385 rac + −

4386 4387 4388 rac + −

4389 4390 4391 rac + −

4392 4393 4394 rac + −

4395 4396 4397 rac + −

4398 4399 4400 rac + −

4401 4402 4403 rac + −

4404 4405 4406 rac + −

4407 4408 4409 rac + −

4410 4411 4412 rac + −

4413 4414 4415 rac + −

4416 4417 4418 rac + −

4419 4420 4421 rac + −

4422 4423 4424 rac + −

4425 4426 4427 rac + −

4428 4429 4430 rac + −

4431 4432 4433 rac + −

4434   4435 4436 4437 4438 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4439 4440 4441 rac + −

4442 4443 4444 rac + −

4445 4446 4447 rac + −

4448 4449 4450 rac + −

4451 4452 4453 rac + −

4454 4455 4456 rac + −

4457 4458 4459 rac + −

4460 4461 4462 rac + −

4463 4464 4465 rac + −

4466 4467 4468 rac + −

4469   4470 4471 4472 4473 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4474   4475 4476 4477 4478 4479 4480 4481 4482 stereoisomer mixture (R, R, R) (S, S, S) (R, R, S) (R, S, S) (R, S, R) (S, S, R) (S, R, R) (S, R, S)

4483   4484 4485 4486 4487 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4488 4489 4490 rac + −

4491 4492 4493 rac + −

Biological Characterization of the Compounds According to the Invention

Progesterone receptor modulators can be identified with the aid of simple methods, test programmes known to the skilled person. It is possible for this purpose for example to incubate a compound to be tested together with a progestogen in a test system for progesterone receptor ligands and to check whether the effect mediated by progesterone is altered in the presence of the modulator in this test system.

The substances according to the invention of the general formula I were tested in the following models:

Progesterone Receptor-Binding Assay Measurement of the Receptor Binding Affinity:

The receptor binding affinity was determined by competitive binding of a specifically binding ³H-labelled hormone (tracer) and of the compound to be tested on receptors in the cytosol from animal target organs. The aim in this case was receptor saturation and reaction equilibrium.

The tracer and increasing concentrations of the compound to be tested (competitor) were coincubated at 0-4° C. for 18 h with the receptor-containing cytosol fraction. After removal of unbound tracer with carbon-dextran suspension, the receptor-bound tracer content was measured for each concentration, and the IC₅₀ was determined from the concentration series. The relative molar binding affinity (RBA) was calculated as ratio of the IC₅₀ values for reference substance and compound to be tested (×100%) (RBA of the reference substance=100%).

The following incubation conditions were chosen for the receptor types:

Progesterone Receptor:

Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mMTris/HCl, pH 7.4; 1 mM ethylenediamine tetraacetate, 2 mM dithiothreitol) with 250 mM sucrose; stored at −30° C. Tracer: ³H-ORG 2058, 5 nM; reference substance: progesterone.

Glucocorticoid Receptor:

Thymus cytosol from the adrenalectomized rat, thymi stored at −30° C.; buffer: TED. Tracer: ³H-dexamethasone, 20 nM; reference substance: dexamethasone.

The competition factors (CF values) for the compounds according to the invention of the general formula (I) on the progesterone receptor are between 0.2 and 35 relative to progesterone. The CF values on the glucocorticoid receptor are in the range from 3 to 35 relative to dexamethasone.

The compounds according to the invention accordingly have a high affinity for the progesterone receptor, but only a low affinity for the glucocorticoid receptor.

Antagonism on the Progesterone Receptor PR

The transactivation assay is carried out as described in WO 02/054064.

The IC₅₀ values are in the range from 0.1 to 150 nM.

Agonism on the Progesterone Receptor PR

The transactivation assay is carried out as described in Fuhrmann et al. (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., Chwalisz K., Journal of Medicinal Chemistry, 43, 26, 2000, 5010-5016).

The table which follows shows, by way of example, results from the transactivation test on antagonistic activity on (PR-B).

TABLE 1 Example No. IC₅₀ mol  2b 1.8E−9  3 5.6E−9  4 2.0E−9  5 7.9E−9  6 5.0E−9 10 7.0E−9 12 1.8E−9 16 1.7E−8 32 2.7E−8 39 1.7E−8 44 8.0E−9

Table 2 shows results from the transactivation test on antagonistic activity at PR-A. Both the efficacy and the IC50 are shown. All substances exhibit significant antagonism. The IC₅₀ values of the inventive compounds shown by way of example in table 2 are in the range of 1-60 nM.

TABLE 2 Efficacy IC50 Example (antagonism at (antagonism at No. Structure PR-A) [%] PR-A) [mol/l] 19a

107.57 6.26E-9  59

103.21 4.68E-8  63

103.64 2.63E-8  68

101.96 5.13E-9  71

100.46 1.73E-8  78

100.76 5.57E-8  84

101.51 5.12E-8  97

105.36 5.56E-8 101a

103.44 1.47E-8 103

98.48 4.88E-8 108

95.98 3.61E-8 111

103.18 4.17E-9 113

97.94 2.17E-8 159

96.21 1.59E-8 162

99.01 4.41E-8 169

103.21 1.7E-9 172

100.63 1.2E-9 199

96.41 3.77E-8 200b

98.5 5.66E-9

Dosage

The progesterone receptor modulators can be administered orally, enterally, parenterally or transdermally for the use according to the invention.

Satisfactory results are generally to be expected in the treatment of the indications mentioned hereinbefore when the daily doses cover a range from 1 μg to 1000 mg of the compound according to the invention for gynaecological indications such as the treatment of endometriosis, leiomyomas of the uterus and dysfunctional bleeding, and for use in fertility control and for hormone replacement therapy. For oncological indications, daily dosages in the range from 1 μg to 2000 mg of the compound according to the invention are to be administered.

Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 μg to 500 mg per day, depending on the age and constitution of the patient, it being possible to administer the necessary daily dose by single or multiple administration.

The dosage range for the compounds according to the invention for the treatment of breast carcinomas is 10 mg to 2000 mg per day.

The pharmaceutical products based on the novel compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, absorbents, diluents, masking flavours, colourants, etc. which are used in pharmaceutical technology, and converting into the desired administration form. Reference should be made in this connection to Remington's Pharmaceutical Science, 15^(th) ed. Mack Publishing Company, East Pennsylvania (1980).

Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions.

Preparations for injection and infusion are possible for parenteral administration.

Appropriately prepared crystal suspensions can be used for intraarticular injection.

Aqueous and oily solutions for injection or suspensions and corresponding depot preparations can be used for intramuscular injection.

For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, both for systemic and for local therapy.

Furthermore, compositions for vaginal use may also be mentioned as preparation.

For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants.

Patches are possible for transdermal administration, and formulations in gels, ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures are possible for topical application. The dosage of the compounds of the general formula I in these preparations should be 0.01%-20% in order to achieve an adequate pharmacological effect.

Corresponding tablets can be obtained for example by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or means to achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of a plurality of layers.

Correspondingly, coated tablets can be produced by coating cores produced in analogy to the tablets with compositions normally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. The tablet covering may in this case also consist of a plurality of layers, it being possible to use the excipients mentioned above for tablets.

Solutions or suspensions of the compounds according to the invention of the general formula I may additionally comprise taste-improving agents such as saccharin, cyclamate or sugar, and, for example, flavourings such as vanillin or orange extract. They may additionally comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.

Capsules comprising the compounds of the general formula I can be produced for example by mixing the compound(s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules.

Suitable suppositories can be produced for example by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts can be used, because of their antagonistic or partial agonistic activity, for the manufacture of a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be employed to counteract hormonal irregularities, for inducing menstruation and alone or in combination with prostaglandins and/or oxytocin to induce labour.

The compounds according to the invention of the general formula (I) or their pharmaceutically acceptable salts are furthermore suitable for the manufacture of products for female contraception (see also WO 93/23020, WO 93/21927).

The compounds according to the invention or their pharmaceutically acceptable salts can additionally be employed alone or in combination with a selective oestrogen receptor modulator (SERM) for female hormone replacement therapy.

In addition, the said compounds have an antiproliferative effect in hormone-dependent tumours. They are therefore suitable for the therapy of hormone-dependent carcinomas such as, for example, for breast, prostate and endometrial carcinomas.

The compounds according to the invention or their pharmaceutically acceptable salts can be employed for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, especially after tamoxifen failure.

The compounds according to the invention, having antagonistic or partially agonistic activity, of the general formula (I) or their pharmaceutically acceptable salts can also be used in combination with compounds having antioestrogenic activity (oestrogen receptor antagonists or aromatase inhibitors) or selective oestrogen receptor modulators (SERM) for producing pharmaceutical products for the treatment of hormone-dependent tumours. The compounds according to the invention can likewise be used in combination with SERMs or an antioestrogen (oestrogen receptor antagonist or aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of the uterus.

Suitable for combination with the non-steroidal progesterone receptor modulators according to the invention in this connection are for example the following antioestrogens (oestrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]propyl}amino)pentyl]-estra-1,3,5(10)-triene-3,17beta-diol (WO98/07740), 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(110)-triene-3,17-beta-diol (WO 99/33855), 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol (WO 03/045972), clomifene, raloxifene, and further compounds having antioestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole or atamestane.

Finally, the present invention also relates to the use of the compounds of the general formula I, where appropriate together with an antioestrogen or SERM, for the manufacture of a medicament.

The present invention further relates to pharmaceutical compositions which comprise at least one compound according to the invention, where appropriate in the form of a pharmaceutically/pharmacologically acceptable salt.

These pharmaceutical compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. Besides conventional carriers and/or diluents, they comprise at least one compound according to the invention.

The medicaments of the invention are manufactured with the conventional solid or liquid carriers or diluents and the excipients normally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner. The preferred preparations consist of a dosage form suitable for oral administration. Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions, where appropriate as depot form.

The pharmaceutical compositions comprising at least one of the compounds according to the invention are preferably administered orally.

Also suitable are parenteral preparations such as solutions for injection. Further preparations which may also be mentioned are for example suppositories and compositions for vaginal use.

Preparation of the Inventive Compounds:

The compounds of the general formula I may be synthesized, for example, as shown in scheme 1. An α-hydroxylation of the ester of the general formula II and subsequent oxidation of the alcohol III formed to the ketone gives rise to compounds of the general formula IV.

For the preparation of compounds of the general formula III by α-hydroxylation of esters, various processes known from the literature are useful (for example Davis et al. in J. Org. Chem., 1984, 49, 3241 using 2-sulphonyloxaziridine). The oxidation to compounds of the general formula IV can then be effected by known standard methods. The amides of the general formula VI are prepared, for example, via the formation of the acid chlorides and subsequent reaction with the corresponding amines. Alternatively, for this purpose, it is also possible to utilize other methods of amide formation according to the amine to be introduced. The compounds of the general formula I are then prepared from the amides of the general formula VI by addition of organometallic compounds such as magnesium, lithium or organozinc compounds. Steps 1-5 can, though, also be performed in an altered sequence.

Some intermediate compounds of the general formulae III-V are commercially available. The substituents A, X, Y, R¹, R², R³ and R⁴ may optionally be modified further after they have been introduced. Possible reactions for this purpose include, for example, oxidation, reduction, alkylations, acylations, nucleophilic additions or else transition metal-catalysed coupling reactions.

Functional groups in compounds of the general formulae II-VI are optionally provided intermediately with protective groups which are then detached again at a suitable stage.

The examples which follow serve to illustrate the subject-matter of the invention in detail without any intention to restrict it to them.

The preparation of 6-amino-4-methyl-2,3-benzoxazin-1-one is described in WO 199854159.

Preparation of 6-(4,4-dimethyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one a) 2-Hydroxy-2-cyclohexylacetic acid ethyl ester

To a solution of 2-cyclohexylacetic acid ethyl ester (1.2 g) in tetrahydrofuran (25 ml) was added, at −70° C., a solution of potassium hexamethyldisilizide (20 ml, 0.5 M in toluene). The mixture was left to stir at −70° C. for a further 30 minutes and then a solution of 3-phenyl-2-phenylsulphonyloxaziridine (2.6 g) in tetrahydrofuran (25 ml) was added. The mixture was left to stir at −70° C. for one hour. The reaction mixture was then poured onto saturated aqueous ammonium chloride solution. The mixture was stirred for a further 30 minutes and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The resulting crude product was chromatographed on silica gel. 1.3 g of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.11-1.27 (6H), 1.31 (3H), 1.44 (1H), 1.61-1.79 (4H), 2.73 (1H), 4.01 (1H), 4.25 (2H).

b) 2-Oxo-2-cyclohexylacetic acid ethyl ester

To a solution of the compounds described under a) in 20 ml of dichloromethane were added 20 ml of a 0.35 molar solution of 1,1-dihydro-1,1,1-triacetoxy-1,2-benzodioxol-3(1H)-one (Dess-Martin periodane) in dichloromethane. The mixture was left to stir at 23° C. for 14 hours. Subsequently, the mixture was diluted with 500 ml of methyl tert-butyl ether and then poured onto 1 l of an aqueous solution of 34 g of sodium hydrogencarbonate and 100 g of sodium thiosulphate. The mixture was left to stir for 30 minutes, then the phases were separated and the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 0.8 g of product was obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.15-1.29 (5H), 1.36 (3H), 1.67-1.91 (5H), 3.03 (1H), 4.32 (2H).

c) 2-Oxo-2-cyclohexylacetic acid

To a solution of the compound described under b) in 13 ml of ethanol was added a solution of 0.5 g of sodium hydroxide in 8 ml of water. The mixture was left to stir at 23° C. for a further 14 hours, then diluted with water and extracted with ethyl acetate. Subsequently, the aqueous phase was acidified with 2 normal hydrochloric acid (pH 4). The mixture was then extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride solution. It was then dried over sodium sulphate and concentrated under reduced pressure. The resulting crude product (0.7 g) was used in the next stage without purification.

d) N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide

The carboxylic acid described under c) was dissolved in 20 ml of N,N-dimethylacetamide. 0.38 ml of thionyl chloride was added at −10° C. and the mixture was left to stir at −10° C. for one hour. Subsequently, 0.92 g of 3-chloro-4-cyanoaniline was added in portions. The mixture was then stirred for a further 3 hours (−10° C. to 0° C.). Subsequently, the reaction mixture was poured on ice-water. It was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with a mixture of hexane/ethyl acetate. 1.2 g of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.22-1.46 (5H), 1.72-1.96 (5H), 3.42-3.50 (1H), 7.59 (1H), 7.67 (1H), 8.02 (1H), 8.96 (1H).

EXAMPLE 1 rac-N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexyl-2-phenylacetamide

A 1 molar solution of phenylmagnesium bromide in tetrahydrofuran (0.9 ml) was diluted with 10 ml of absolute tetrahydrofuran. The mixture was cooled to −70° C. and then a solution of 100 mg of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide in 6 ml of tetrahydrofuran was added. Subsequently, the mixture was left to stir at −70° C. for a further 2.5 hours. The reaction mixture was then poured onto ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 130 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 0.84 (1H), 1.10-1.43 (5H), 1.71-1.84 (4H), 2.60 (2H), 7.29-7.42 (3H), 7.48 (1H), 7.57 (1H), 7.65 (2H), 7.96 (1H), 8.95 (1H).

EXAMPLE 2 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-phenylethynyl-acetamide

To a solution of 94 μl of phenylacetylene in tetrahydrofuran (5 ml) was added, at −78° C., n-butyllithium (540 μl, 1.6 M in hexane). The mixture was left to stir at this temperature for a further 30 minutes and then a solution of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (100 mg) in 5 ml of tetrahydrofuran was added dropwise. Subsequently, the mixture was allowed to come to 23° C. over approx. 3 h and then stirred for a further 10 h. The reaction mixture was then poured onto ice-cold saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 110 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 0.84 (1H), 1.14-1.28 (5H), 1.60-1.98 (6H), 6.86 (1H), 7.36-7.46 (5H), 7.94 (2H), 8.27 (1H), 10.41 (1H).

EXAMPLE 2A AND 2B (+)-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-phenylethynyl-acetamide 2a and (−)-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-phenylethynylacetamide 2b

The racemic mixture obtained in Example 2 was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 2a and 2b.

2a: [α]^(D) ₂₀: +2.30 (CHCl₃, 11.3 mg/l ml; λ=589 nM)

2b: [α]^(D) ₂₀: −2.00 (CHCl₃, 11.0 mg/1 ml; λ=589 nM)

EXAMPLE 3 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-3-phenylpropanamide

A 2 molar solution of benzylmagnesium chloride in tetrahydrofuran (430 μl) was diluted with 4 ml of absolute tetrahydrofuran. The mixture was cooled to −70° C. and then a solution of 100 mg of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide in 6 ml of tetrahydrofuran was added. Subsequently, the mixture was left to stir at −70° C. for a further 2 hours. The reaction mixture was then poured onto ice-cold saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 78 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.01-1.76 (10H), 1.93 (1H), 2.87 (1H), 3.02 (1H), 5.46 (1H), 7.05-7.28 (5H), 7.69-7.78 (2H), 8.01 (1H), 9.69 (1H).

EXAMPLE 4 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-methyl phenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (100 mg) was reacted with 4-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 45 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.16-1.35 (5H), 1.66-1.88 (4H), 2.05-2.14 (2H), 2.35 (3H), 3.02 (1H), 7.13 (2H), 7.35 (2H), 7.56 (1H), 7.62 (1H), 7.98 (1H), 8.80 (1H).

EXAMPLE 5 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-trifluoromethyl-phenyl)ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-trifluoromethylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.12-1.39 (5H), 1.64-1.90 (4H), 2.08-2.16 (2H), 3.08 (1H), 7.54-7.65 (6H), 7.99 (1H), 8.80 (1H).

EXAMPLE 6 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-fluorophenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-fluorophenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.21-1.37 (5H), 1.64-1.91 (4H), 2.05-2.16 (2H), 2.95 (1H), 7.02 (2H), 7.45 (2H), 7.56 (1H), 7.64 (1H), 7.98 (1H), 8.79 (1H).

EXAMPLE 7 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-formylphenyl)-ethynylacetamide 7a) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-(1,3-dioxolanyl)-phenyl)ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 4-(1-3-dioxolanyl)phenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 180 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.07-1.25 (5H), 1.56-1.95 (6H), 3.88-4.03 (4H), 5.70 (1H), 6.86 (1H), 7.42 (4H), 7.91 (2H), 8.24 (1H), 10.38 (1H).

7b) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-formylphenyl)ethynyl-acetamide

To a solution of the compound described under 7a (50 mg) in methanol (2 ml) was added HCl (1 M in water, 0.4 ml) at 23° C. The mixture was left to stir at 23° C. for a further 24 hours. The reaction mixture was then poured onto saturated sodium hydrogen carbonate solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 20 mg of product 7b and 23 mg of the following product 7c were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.10-1.30 (5H), 1.64-1.79 (4H), 1.94-1.99 (2H), 7.66 (2H), 7.89-7.97 (4H), 8.26 (1H), 10.02 (1H).

7c) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-(1,1-dimethoxyacetyl)-phenyl)ethynylacetamide

Compound 7c was obtained as a by-product in the purification of 7b.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.11-1.29 (5H), 1.62-1.78 (4H), 1.92-1.99 (2H), 3.24 (6H), 5.40 (1H), 7.39 (2H), 7.46 (2H), 7.80 (1H), 7.96 (1H), 8.26 (1H).

EXAMPLE 8 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(3-methyl phenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 3-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 140 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.22-1.42 (5H), 1.73-1.94 (4H), 2.09-2.19 (2H), 2.37 (3H), 3.07 (1H), 7.20-7.33 (4H), 7.60 (1H), 7.67 (1H), 8.02 (1H), 8.84 (1H).

EXAMPLE 9 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(2-methyl phenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with 2-methylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 160 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.22-1.37 (5H), 1.70-1.90 (4H), 2.05-2.16 (2H), 2.45 (3H), 3.07 (1H), 7.15 (1H), 7.20-7.29 (3H), 7.43 (1H), 7.56 (1H), 7.64 (1H), 7.98 (1H), 8.81 (1H).

EXAMPLE 10 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-hydroxyphenyl)-ethynylacetamide 10a) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-methoxyphenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (750 mg) was reacted with 4-methoxyphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 1 g of product was obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.13-1.37 (5H), 1.66-1.89 (4H), 2.05-2.16 (2H), 3.08 (1H), 3.82 (3H), 6.85 (2H), 7.40 (2H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.83 (1H).

10b) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-hydroxyphenyl)-ethynylacetamide

To a solution of the compound described in 10a (200 mg) in dichloromethane (6 ml) was added boron tribromide (1 M in dichloromethane, 2.8 ml) at −15° C. The reaction mixture was left to warm at 23° C. over 3 hours and left to stir over a further 24 hours. The reaction mixture was then poured onto ice-cold saturated sodium hydrogencarbonate solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 81 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.16-1.43 (5H), 1.65-1.98 (5H), 2.44 (1H), 3.20 (1H), 5.22 (1H), 6.55 (1H), 6.78 (2H), 7.19 (2H), 7.44 (1H), 7.70 (1H), 8.14 (1H).

EXAMPLE 11 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(1-hydroxypropynyl)-acetamide 11a) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(1-(2-tetrahydro-pyranyloxy)propynyl)acetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) was reacted with tetrahydro-2-(2-propynyloxy)-2H-pyran and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 190 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.06-1.20 (5H), 1.43-1.87 (12H), 3.39-3.44 (1H), 3.66-3.73 (1H), 4.25 (2H), 4.74 (1H), 7.89 (2H), 8.19 (1H).

11b) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(1-hydroxypropynyl)-acetamide

To a solution of the compound described in 11a (50 mg) in acetone (2 ml) was added HCl (1 M in water, 0.4 ml) at 23° C. The mixture was left to stir at 23° C. for a further 24 hours. Thereafter, the reaction mixture was poured onto saturated sodium hydrogencarbonate solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 40 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.05-1.23 (5H), 1.49-1.93 (6H), 4.13 (2H), 5.22 (1H), 6.66 (1H), 7.89-7.97 (2H), 8.24 (1H), 10.30 (1H).

EXAMPLE 12 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-carboxyphenyl)-ethynylacetamide 12a) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-carbomethoxy-phenyl)ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (140 mg) was reacted with 4-ethynylbenzoic acid methyl ester and lithium diisopropylamide in tetrahydrofuran in analogy to Example 2. After column chromatography, 130 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.07-1.26 (5H), 1.58-1.72 (4H), 1.87-1.95 (2H), 3.82 (3H), 6.93 (1H), 7.55 (2H), 7.86-7.95 (4H), 8.23 (1H), 10.41 (1H).

12b) rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(4-carboxyphenyl)-ethynylacetamide

To a solution of the compound described in 12a (50 mg) in methanol (1.5 ml) was added a solution of potassium carbonate (100 mg) in water (50 μl) at 23° C. The mixture was left to stir at 23° C. for a further 4 days. The reaction mixture was then warmed to 40° C. and left to stir for a further 4 hours. The reaction mixture was then poured onto saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. The crude product was chromatographed on silica gel. 28 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.02-1.31 (5H), 1.58-1.76 (4H), 1.87-1.95 (2H), 6.93 (1H), 7.53 (2H), 7.86-7.95 (4H), 8.23 (1H), 10.41 (1H), 13.11 (1H).

EXAMPLE 13 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(2,5-dimethylphenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (150 mg) were reacted with 2,5-dimethylphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 190 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.14-1.38 (5H), 1.70-1.90 (4H), 2.05-2.16 (2H), 2.29 (3H), 2.40 (3H), 3.07 (1H), 7.09 (2H), 7.25 (1H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.82 (1H).

EXAMPLE 14 rac-N-(3-Chloro-4-cyanophenyl)-2-hydroxy-2-cyclohexyl-2-(3-methoxyphenyl)-ethynylacetamide

N-(3-Chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (750 mg) was reacted with 3-methoxyphenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 1.0 g of product was obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.14-1.38 (5H), 1.66-1.90 (4H), 2.10-2.18 (2H), 3.15 (1H), 3.80 (3H), 6.92 (1H), 6.98 (1H), 7.06 (1H), 7.22 (1H), 7.56 (1H), 7.63 (1H), 7.98 (1H), 8.83 (1H).

EXAMPLE 15 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-m-tolylpropionamide

The preparation was effected analogously to Example 3 with 3-methylbenzylmagnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.0-2.2 (m, 11H), 2.20 (s, 1H), 2.29 (s, 3H), 2.90 (d, 1H), 3.45 (d, 1H), 6.97-7.33 (m, 4H), 7.41 (dd, 1H), 7.60 (d, 1H), 7.85 (d, 1H), 8.56 (s, 1H).

EXAMPLE 16 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-(4-methoxyphenyl)-propionamide

The preparation was effected analogously to Example 3 with 4-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.09-1.40 (m, 5H), 1.63-2.04 (m, 6H), 2.11 (s, 1H), 2.83 (d, 1H), 3.38 (d, 1H), 3.75 (s, 3H), 6.80 (d, 2H), 7.07 (d, 2H), 7.37 (dd, 1H), 7.55 (d, 1H), 7.84 (d, 1H), 8.54 (s, 1H).

EXAMPLE 17 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-(3-methoxyphenyl)-propionamide

The preparation was effected analogously to Example 3 with 3-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.05-1.40 (m, 5H), 1.60-2.05 (m, 6H), 2.88 (d, 1H), 3.30 (d, 1H), 3.70 (s, 3H), 6.75 (m, 3H), 7.16 (dd, 1H), 7.40 (dd, 1H), 7.55 (d, 1H), 7.82 (d, 1H), 8.75 (s, 1H).

EXAMPLE 18 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-(3-iodophenyl)-propionamide

35 ml of 3-iodobenzylzinc bromide solution (0.5M in THF) were initially charged in 15 ml of THF and cooled to −75° C. 1.0 g of N-(3-chloro-4-cyanophenyl)-2-cyclohexyl-2-oxoacetamide, dissolved in 15 ml of THF, was added dropwise. The mixture was stirred at −75° C. for 4 h and at room temperature for a further hour, then added to sat. ammonium chloride solution and extracted with ethyl acetate. The organic phases were washed with sat. NaCl solution and dried over sodium sulphate. The crude product was purified by chromatography and then recrystallized from hexane/diisopropyl ether. 338 mg of the desired product were obtained as a colourless solid. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.0-1.4 (m, 5H), 1.6-2.0 (m, 6H), 2.03 (s, 1H), 2.85 (d, 1H), 3.27 (d, 1H), 6.97 (dd, 1H), 7.12 (d, 1H), 7.36 (dd, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 8.46 (s, 1H).

EXAMPLE 19 rac-3-(4′-Acetylbiphenyl-2-yl)-N-(3-chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-propionamide

rac-N-(3-Chloro-4-cyanophenyl)-2-cyclohexyl-2-hydroxy-3-(2-iodophenyl)propionamide was prepared analogously to Example 18.

390 mg of the iodine compound and 197 mg of 4-acetylphenylboronic acid were initially charged in 6 ml of 1:1 toluene/ethanol, and 1.5 ml of 1M sodium carbonate solution and 90 mg of tetrakis(triphenylphosphine)palladium were added. The mixture was heated at 120° C. in a microwave for 25 min, then filtered through Celite and rinsed with ethyl acetate. The solution was washed with sat. NaCl solution, dried over sodium sulphate and concentrated. The crude product was purified by chromatography. 137 mg of the desired product were obtained as a colourless foam. ¹H NMR (ppm, DMSO-D₆, 400 MHz): 0.95-1.35 (m, 5H), 1.50-1.80 (m, 6H), 2.63 (s, 3H), 3.03 (d, 1H), 3.16 (d, 1H), 7.09 (m, 1H), 7.23 (m, 2H), 7.46 (d, 2H), 7.59 (m, 1H), 7.76 (dd, 1H), 7.84 (d, 1H), 7.97 (d, 2H), 8.05 (d, 1H), 9.91 (s, 1H).

The racemic mixture obtained was separated into the enantiomers 19a and 19b by preparation chiral HPLC (column Chiralpak 1A 5μ 250×200 mm eluent hexane/ethanol 85:15).

EXAMPLE 19B

R_(t)=−11.6 min.

EXAMPLE 20 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-phenyl-propionamide

The preparation was effected analogously to Example 3 from N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-oxoacetamide (prepared analogously to N-(3-chloro-4-cyanophenyl)-2-cyclohexyl-2-oxoacetamide, see above) and benzylmagnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.05-1.40 (m, 5H), 1.65-2.05 (m, 6H), 2.15 (s, 1H), 2.92 (d, 1H), 3.41 (d, 1H), 7.16 (m, 2H), 7.24 (m, 3H), 7.73 (d, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.63 (s, 1H).

The racemic mixture obtained was separated into the enantiomers 20a and 20b by preparative chiral HPLC (column: Chiralpak AD 250×10 mm).

Example 20a: [α]^(D) ₂₀=−129.4° (MeOH, c=1.01) Example 20b: [α]^(D) ₂₀=+132.7° (MeOH, c=1.00)

EXAMPLE 21 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-m-tolyl-propionamide

The preparation was effected analogously to Example 20 with 3-methylbenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.2-1.5 (m, 5H), 1.6-2.1 (m, 6H), 2.20 (s, 1H), 2.28 (s, 3H), 2.94 (d, 1H), 3.42 (d, 1H), 7.0-7.3 (m, 4H), 7.85 (m, 3H), 8.68 (s, 1H).

EXAMPLE 22 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-p-tolyl-propionamide

The preparation was effected analogously to Example 20 with 4-methylbenzyl-magnesium chloride. ¹H NMR (ppm, DMSO-D₆, 400 MHz): 1.0-1.3 (m, 5H), 1.4-1.8 (m, 6H), 2.12 (s, 1H), 2.23 (s, 3H), 2.84 (d, 1H), 2.98 (d, 1H), 7.0-7.3 (m, 4H), 7.97 (d, 1H), 8.11 (dd, 1H), 8.23 (d, 1H), 9.90 (s, 1H).

EXAMPLE 23 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-(4-methoxy-phenyl)propionamide

The preparation was effected analogously to Example 20 with 4-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.10-1.45 (m, 5H), 1.65-2.05 (m, 6H), 2.19 (s, 1H), 2.90 (d, 1H), 3.42 (d, 1H), 3.79 (s, 3H), 6.84 (d, 2H), 7.12 (d, 2H), 7.79 (d, 1H), 7.88 (dd, 1H), 7.94 (d, 1H), 8.71 (s, 1H).

The resulting racemic mixture was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 23a and 23b.

Example 23a: R_(t)=5.41 min

(Chiralpak IA 5μ 150×4.6, 80% hexane/20% 2-propanol, 1 ml/min)

Example 23b: R_(t), =6.36 min

(Chiralpak Ia 5μ 150×4.6, 80% Hexane/20% 2-Propanol, 1 ml/min)

EXAMPLE 24 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-(3-methoxy-phenyl)propionamide

The preparation was effected analogously to Example 3 with 4-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.0-2.0 (m, 11H), 2.88 (d, 1H), 2.97 (d, 1H), 3.56 (s, 3H), 5.44 (s, 1H), 6.58 (m, 1H), 6.74 (m, 2H), 7.00 (dd, 1H), 8.17 (dd, 1H), 8.27 (d, 1H), 9.92 (s, 1H).

EXAMPLE 25 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-(2-iodophenyl)propionamide

The preparation was effected analogously to Example 18 using 2-iodobenzylzinc bromide. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.0-1.4 (m, 5H), 1.6-2.0 (m, 6H), 2.03 (s, 1H), 2.85 (d, 1H), 3.27 (d, 1H), 6.97 (dd, 1H), 7.12 (d, 1H), 7.36 (dd, 1H), 7.55 (m, 3H), 7.79 (s, 1H), 8.46 (s, 1H).

EXAMPLE 26 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-(3-iodophenyl)propionamide

The preparation was effected analogously to Example 25 using 3-iodobenzylzinc bromide. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.05-1.40 (m, 5H), 1.60-2.05 (m, 6H), 2.06 (s, 1H), 2.86 (d, 1H), 3.27 (d, 1H), 6.96 (m, 1H), 7.12 (m, 1H), 7.55 (d, 2H), 7.76 (m, 2H), 7.87 (s, 1H), 8.58 (s, 1H).

The racemic mixture obtained was separated into the enantimers 26a and 26b by preparation chiral HPLC (column Chiralpak 1A 5μ 250×20 mm, eluent hexane/ethanol 95:5).

Example 26a: R_(t), =15.1-17.4 min

Example 26b:

EXAMPLE 27 rac-3-(4′-Acetylbiphenyl-2-yl)-N-(4-cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxypropionamide

The preparation was effected analogously to Example 19 using the compound prepared in Example 25. ¹H NMR (ppm, DMSO-D₆, 400 MHz): 0.90-1.25 (m, 5H), 1.45-1.80 (m, 6H), 2.57 (s, 3H), 3.01 (d, 1H), 3.13 (d, 1H), 5.49 (s, 1H), 7.04 (dd, 1H), 7.17 (m, 2H), 7.39 (d, 2H), 7.91 (d, 2H), 8.00 (m, 2H), 8.05 (m, 1H), 8.26 (d, 1H), 10.07 (s, 1H).

The racemic mixture obtained was separated into the enantimers 27a and 27b by preparation chiral HPLC (column Chiralpak OD-H5μ 250×20 mm, eluent hexane/2-propanoll 98:15).

Example 27a: Rt=8.1-10.4 min

Example 27b: Rt=10.8-13.4 min

EXAMPLE 28 rac-3-(4′-Acetylbiphenyl-3-yl)-N-(4-cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxypropionamide

The preparation was effected analogously to Example 19 using the compound prepared in Example 26. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.05-1.45 (m, 5H), 1.65-2.10 (m, 6H), 2.22 (s, 1H), 2.63 (s, 3H), 3.01 (d, 1H), 3.44 (d, 1H), 7.20 (m, 1H), 7.35 (m, 1H), 7.44 (m, 1H), 7.50 (d, 2H), 7.69 (m, 3H), 7.90 (m, 1H), 7.95 (d, 2H), 8.64 (s, 1H).

The racemic mixture obtained was separated into the enantimers 28a and 28b by preparation chiral HPLC (column Chiralpak 1A5μ 250×20 mm, hexane/ethanol 8:2).

Example 28a: [α]^(D) ₂₀=−49.6° (MeOH, c=1.0)

Example 28b: [α]^(D) ₂₀=???° (MeOH, c=1.0)

EXAMPLE 29 rac-6-[2-Cyclohexyl-2-hydroxy-2-(phenylethynyl)ethanoylamino]-4-methyl-2,3-benzoxazin-1-one 29a) rac-6-[2-Cyclohexyl-2-oxoethanoylamino]-4-methyl-2,3-benzoxazin-1-one

2-Oxo-2-cyclohexylacetic acid (200 mg) was reacted with 6-amino-4-methyl-2,3-benzoxazin-1-one and thionyl chloride in N,N-dimethylacetamide in analogy to Example d. After column chromatography, 360 mg of product were obtained.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.23-1.51 (5H), 1.73-1.98 (5H), 2.61 (3H), 3.45-3.53 (1H), 7.84 (1H), 8.36 (1H), 8.39 (1H), 9.19 (1H).

29b) rac-6-[2-Cyclohexyl-2-hydroxy-2-(phenylethynyl)ethanoylamino]-4-methyl-2,3-benzoxazin-1-one

6-[2-Cyclohexyl-2-oxoethanoylamino]-4-methyl-2,3-benzoxazin-1-one (200 mg) was reacted with phenylethyne and n-butyllithium in tetrahydrofuran in analogy to Example 2. After column chromatography, 160 mg of product were obtained.

¹H NMR (ppm, DMSO-d₆, 400 MHz): 1.00-1.32 (5H), 1.58-1.77 (4H), 1.93-2.02 (2H), 2.47 (3H), 6.86 (1H), 7.34-7.43 (5H), 8.19 (1H), 8.37-8.41 (2H), 10.50 (1H).

EXAMPLE 30 rac-2-Cyclohexyl-2-hydroxy-N-(4-methyl-1-oxo-1H-benzo[d][1,2]oxazin-6-yl)-3-phenylpropionamide

The preparation was effected analogously to Example 3 using the keto amide described in Example 29a and benzylmagnesium chloride. ¹H NMR (ppm, DMSO-D₆, 400 MHz): 1.00-1.35 (m, 5H), 1.45-1.85 (m, 5H), 1.95 (m, 1H), 2.40 (s, 3H), 2.90 (d, 1H), 3.06 (d, 1H), 5.48 (s, 1H), 7.00-7.25 (m, 5H), 8.06 (m, 1H), 8.10 (s, 1H), 8.25 (dd, 1H), 9.81 (s, 1H).

The resulting racemic mixture was separated by preparative chiral HPLC (column: Chiralpak AD 250×10 mm) into enantiomers 30a and 30b.

Example 30a: [α]^(D) ₂₀=−119.4° (DMSO, c=0.54)

Example 30b: [α]^(D) ₂₀=+113.5° (DMSO, c=0.57)

EXAMPLE 31 rac-2-Cyclohexyl-2-hydroxy-3-(4-methoxyphenyl)-N-(4-methyl-1-oxo-1H-benzo[d][1,2]oxazin-6-yl)propionamide

The preparation was effected analogously to Example 30 using 4-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.12-1.47 (m, 5H), 1.55-2.14 (m, 6H), 2.23 (s, 1H), 2.64 (s, 3H), 2.92 (d, 1H), 3.44 (d, 1H), 3.86 (s, 3H), 6.83 (d, 2H), 7.14 (d, 2H), 7.62 (dd, 1H), 8.25 (d, 1H), 8.31 (d, 1H), 8.81 (s, 1H).

EXAMPLE 32 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-phenylpropionamide

The compound was obtained analogously to Example 3 by reacting N-(3-chloro-4-cyanophenyl)-2-cyclopentyl-2-oxoacetamide (obtained analogously to the corresponding cyclohexyl compound, ¹H NMR (ppm, CDCl₃, 400 MHz): 1.71 (m, 4H), 1.82 (m, 2H), 2.01 (m, 2H), 3.85 (m, 1H), 7.60 (dd, 1H), 7.68 (d, 1H), 8.03 (d, 1H), 9.01 (s, 1H)) with benzylmagnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.95 (m, 8H), 2.50 (m, 1H), 2.84 (d, 1H), 3.50 (d, 1H), 7.16 (m, 2H), 7.27 (m, 3H), 7.37 (dd, 1H), 7.55 (d, 1H), 7.82 (d, 1H), 8.52 (s, 1H).

EXAMPLE 33 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-p-tolylpropionamide

The preparation was effected analogously to Example 32 with 4-methylbenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.75 (m, 7H), 1.87 (m, 1H), 2.15 (s, 1H), 2.29 (s, 3H), 2.48 (m, 1H), 2.79 (d, 1H), 3.48 (d, 1H), 7.06 (m, 4H), 7.39 (dd, 1H), 7.56 (d, 1H), 7.83 (d, 1H), 8.55 (s, 1H).

EXAMPLE 34 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-m-tolylpropionamide

The preparation was effected analogously to Example 32 with 3-methylbenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.73 (m, 7H), 1.85 (m, 1H), 2.17 (s, 1H), 2.25 (s, 3H), 2.49 (m, 1H), 2.79 (d, 1H), 3.48 (d, 1H), 6.95 (m, 2H), 7.05 (d, 1H), 7.16 (m, 1H), 7.38 (dd, 1H) 7.56 (d, 1H), 7.82 (d, 1H), 8.53 (s, 1H).

EXAMPLE 35 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-(4-methoxyphenyl)-propionamide

The preparation was effected analogously to Example 32 with 4-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.46-1.79 (m, 7H), 1.91 (m, 1H), 2.17 (s, 1H), 2.52 (m, 1H), 2.81 (d, 1H), 3.50 (d, 1H), 3.80 (s, 3H), 6.85 (m, 2H), 7.12 (m, 2H), 7.44 (dd, 1H), 7.61 (d, 1H), 7.89 (d, 1H), 8.61 (s, 1H).

EXAMPLE 36 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-(3-methoxyphenyl)-propionamide

The preparation was effected analogously to Example 32 with 3-methoxybenzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.46-1.72 (m, 7H), 1.87 (m, 1H), 2.20 (s, 1H), 2.49 (m, 1H), 2.80 (d, 1H), 3.50 (d, 1H), 3.69 (s, 3H), 6.75 (m, 3H), 7.19 (m, 1H), 7.40 (dd, 1H), 7.56 (d, 1H), 7.84 (d, 1H), 8.58 (s, 1H).

EXAMPLE 37 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-(3-fluorophenyl)-propionamide

The preparation was effected analogously to Example 18, except using 3-fluorobenzyl-zinc chloride solution and N-(3-chloro-4-cyanophenyl)-2-cyclopentyl-2-oxoacetamide (see Example 32). ¹H NMR (ppm, CDCl₃, 400 MHz): 1.40-1.75 (m, 7H), 1.87 (m, 1H), 2.10 (s, 1H), 2.51 (m, 1H), 2.84 (d, 1H), 3.45 (d, 1H), 6.93 (m, 3H), 7.21 (m, 1H), 7.38 (m, 1H), 7.56 (d, 1H), 7.81 (d, 1H), 8.53 (s, 1H).

EXAMPLE 38 rac-N-(3-Chloro-4-cyanophenyl)-2-cyclopentyl-2-hydroxy-3-(3-chlorophenyl)-propionamide

The preparation was effected analogously to Example 37 using 3-chlorobenzylzinc chloride solution. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.41-1.75 (m, 7H), 1.89 (m, 1H), 2.09 (s, 1H), 2.52 (m, 1H), 2.81 (d, 1H), 3.40 (d, 1H), 7.04 (m, 1H), 7.19 (m, 3H), 7.39 (m, 1H), 7.56 (m, 1H), 7.80 (d, 1H), 8.51 (s, 1H).

EXAMPLE 39 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-phenyl-propionamide

The compound was obtained analogously to Example 32 by reacting N-(4-cyano-3-trifluoromethylphenyl)-2-cyclopentyl-2-oxoacetamide (obtained analogously to the corresponding compound with Cl substitents, ¹H NMR (ppm, CDCl₃, 400 MHz): 1.60-1.87 (m, 7H), 1.99 (m, 1H), 3.84 (m, 1H), 7.84 (d, 1H), 7.99 (dd, 1H), 8.16 (d, 1H), 9.12 (s, 1H)) with benzylmagnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.75 (m, 7H), 1.89 (m, 1H), 2.16 (s, 1H), 2.52 (m, 1H), 2.85 (d, 1H), 3.50 (d, 1H), 7.17 (dd, 2H), 7.28 (m, 3H), 7.74 (d, 1H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.65 (s, 1H).

EXAMPLE 40 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-p-tolyl-propionamide

The preparation was effected analogously to Example 33. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.48-1.72 (m, 7H), 1.89 (m, 1H), 2.18 (s, 1H), 2.28 (s, 3H), 2.49 (m, 1H), 2.81 (d, 1H), 3.48 (d, 1H), 7.06 (m, 4H), 7.75 (d, 1H), 8.86 (m, 2H), 8.67 (s, 1H).

EXAMPLE 41 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-m-tolyl-propionamide

The preparation was effected analogously to Example 34. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.75 (m, 7H), 1.89 (m, 1H), 2.19 (s, 1H), 2.24 (s, 3H), 2.51 (m, 1H), 2.80 (d, 1H), 3.47 (d, 1H), 6.96 (m, 2H), 7.05 (d, 1H), 7.16 (m, 1H), 7.75 (d, 1H) 7.83 (dd, 1H), 7.88 (d, 1H), 8.66 (s, 1H).

EXAMPLE 42 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-(4-methoxy-phenyl)propionamide

The preparation was effected analogously to Example 35. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.50-1.75 (m, 7H), 1.93 (m, 1H), 2.21 (s, 1H), 2.53 (m, 1H), 2.83 (d, 1H), 3.51 (d, 1H), 3.79 (s, 3H), 6.85 (m, 2H), 7.13 (d, 2H), 7.79 (d, 1H), 7.90 (dd, 1H), 7.95 (d, 1H), 8.73 (s, 1H).

EXAMPLE 43 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-(3-methoxy-phenyl)propionamide

The preparation was effected analogously to Example 36. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.46-1.73 (m, 7H), 1.88 (m, 1H), 2.23 (s, 1H), 2.50 (m, 1H), 2.81 (d, 1H), 3.49 (d, 1H), 3.68 (s, 3H), 6.69-6.80 (m, 3H), 7.19 (dd, 1H), 7.74 (d, 1H), 7.84 (dd, 1H), 7.91 (d, 1H), 8.70 (s, 1H).

EXAMPLE 44 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclopentyl-2-hydroxy-3-phenyl-propionamide

The compound was obtained analogously to Example 32 by reacting 2-cyclopentyl-N-(4-methyl-1-oxo-1H-benzo[d][1,2]oxazin-6-yl)-2-oxoacetamide (obtained analogously to the corresponding cyclohexyl compound from Example 15^(a)), ¹H NMR (ppm, CDCl₃, 400 MHz): 1.71 (m, 4H), 1.82 (m, 2H), 2.01 (m, 2H), 2.61 (s, 3H), 3.86 (m, 1H), 7.84 (dd, 1H), 8.35 (d, 1H), 8.38 (d, 1H), 9.21 (s, 1H)) with benzylmagnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.50-1.80 (m, 7H), 1.96 (m, 1H), 2.25 (s, 1H), 2.59 (m, 1H), 2.63 (s, 3H), 2.93 (d, 1H), 3.57 (d, 1H), 7.21-7.43 (m, 5H), 7.61 (dd, 1H), 8.25 (d, 1H), 8.32 (d, 1H), 8.79 (s, 1H).

EXAMPLE 45 rac-N-(4-Cyano-3-trifluoromethyl phenyl)-2-hydroxy-2-hydroxy-3-phenyl-2-(tetra-hydropyran-4-yl)propionamide

a) Acetoxy(tetrahydropyran-4-ylidene)acetic acid ethyl ester

7.0 g of ethyl acetoxy(diethoxyphosphoryl)acetate were initially charged in 25 ml of THF, 1.06 g of lithium chloride were added and the mixture was cooled to 0° C. 3.1 ml of N,N,N′,N′-tetramethylguanidine were added dropwise and the mixture was stirred for 15 min. 2.46 g of tetrahydro-4H-pyran-4-one, dissolved in 10 ml of THF, were then added dropwise. The mixture was allowed to come to room temperature and stirred for 18 h. The mixture was partitioned between ethyl acetate and water, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on silica gel. 3.37 g of the desired intermediate were obtained as a yellowish liquid. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.28 (t, 3H), 2.21 (s, 3H), 2.36 (t, 2H), 2.98 (t, 2H), 3.75 (m, 4H), 4.21 (q, 2H).

b) Oxo(tetrahydropyran-4-yl)acetic acid

870 mg of acetoxy(tetrahydropyran-4-ylidene)acetic acid ethyl ester were added to 8 ml of 1M sodium hydroxide solution in 2:1 ethanol/water. The mixture was left to stir at room temperature for 15 min, then diluted with cold water, acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. 540 mg of oxo(tetrahydropyran-4-yl)acetic acid were obtained as a colourless crystalline solid. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.77 (m, 2H), 1.89 (m, 2H), 3.45 (m, 1H), 3.56 (m, 2H), 4.07 (m, 2H), 8.76 (br s, 1H).

c) N-(4-Cyano-3-trifluoromethylphenyl)-2-oxo-2-(tetrahydropyran-4-yl)acetamide

The preparation was effected analogously to the corresponding cyclohexyl compound (see above) from oxo(tetrahydropyran-4-yl)acetic acid, 4-cyano-3-trifluoromethylaniline and thionyl chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.75 (m, 2H), 1.85 (m, 2H), 3.55 (m, 2H), 3.68 (m, 1H), 4.05 (m, 2H), 7.86 (d, 1H), 7.98 (dd, 1H), 8.17 (d, 1H), 9.08 (s, 1H).

d) rac-N-(4-Cyano-3-trifluoromethylphenyl)-2-hydroxy-2-hydroxy-3-phenyl-2-(tetrahydro-pyran-4-yl)propionamide

The preparation was effected analogously to Example 20 from N-(4-cyano-3-trifluoromethylphenyl)-2-oxo-2-(tetrahydropyran-4-yl)acetamide and benzyl-magnesium chloride. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.87 (m, 4H), 2.19 (m, 1H), 2.25 (s, 1H), 2.88 (d, 1H), 3.40 (m, 2H), 3.46 (d, 1H), 4.01 (dd, 1H), 4.10 (dd, 1H), 7.17 (m, 2H), 7.28 (m, 3H), 7.75 (d, 1H), 7.82 (d, 1H), 7.88 (d, 1H), 8.64 (s, 1H).

EXAMPLES 46 TO 55

Analogously to example 27, using the method used in example 19, the following compounds were prepared. Separation into the corresponding enantiomers was effected, where appropriate, by chiral HPLC:

MS (ESI+) Example Structure Name m/z (M + 1) Example 46

3-(3′-Acetylbiphenyl-2-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxypropionamide 535 Example 47

3-(3′-Cyanobiphenyl-2-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxypropionamide 518 Example 48

3-(4′-Cyanobiphenyl-2-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxypropionamide 518 Example 49

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(2-pyridin- 3-ylphenyl)propionamide 494 Example 50

N-(4-Cyano-3-trifluoromethyl- phenyl)-2-cyclohexyl-2-hydroxy- 3-(2-pyridin-4-ylphenyl)propionamide 494 Example 51

N-(4-Cyano-3-trifluoromethyl- phenyl)-2-cyclohexyl-2-hydroxy- 3-(2-thiophen-3-ylphenyl)- propionamide 499 Example 52

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(2-thiophen- 2-yl-phenyl)propionamide 499 Example 53

2′-[2-(4-Cyano-3-trifluoromethyl- phenylcarbamoyl)-2-cyclohexyl- 2-hydroxyethyl]biphenyl-3- carboxylic acid 537 Example 54

N-(2-Dimethylaminoethyl)-2′- [2-(4-cyano-3-trifluoromethyl- phenylcarbamoyl)-2-cyclohexyl- 2-hydroxyethyl]biphenyl-3- carboxamide 607 Example 55

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(3′-methane- sulfonylaminobiphenyl-2-yl)propionamide 586

EXAMPLES 56 TO 78

Analogously to example 26, using the method used in example 28, the following compounds were prepared:

MS (ESI+) Example Structure Name m/z (M + 1) Example 56

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-[4′-(1,2-dihydroxyethyl)- biphenyl-3-yl]-2-hydroxypropionamide 553 Example 57

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-(4′-fluorobiphenyl-3- yl)-2-hydroxypropionamide 511 Example 58

3-(2′-Acetylbiphenyl-3-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxypropionamide 535 Example 59

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(3-thiophen- 3-ylphenyl)propionamide 499 Example 60

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-cyclo- hexyl-2-hydroxyethyl]biphenyl-4- carboxamide 550 Example 61

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-[4′-(methane- sulfonylaminomethyl)biphenyl-3-yl]- propionamide 600 Example 62

3-(4′-Acetylaminobiphenyl-3-yl)-N- (4-cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxypropionamide 550 Example 63

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(4′-methyl- sulfamoylbiphenyl-3-yl)propionamide 586 Example 64

N-(4-Cyano-3-trifluormethylphenyl)- 2-cyclohexyl-3-(4′-dimethylsulfamoyl- biphenyl-3-yl)-2-hydroxypropionamide 600 Example 65

N-(4-Cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxy-3-[4′-(5-hydroxy- 5-trifluoromethyl-4,5-dihydroisoxazol- 3-yl)biphenyl-3-yl]propionamide 646 Example 66

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(3′-methane- sulfonylaminobiphenyl-3-yl)propionamide 586 Example 67

3′-[2-(4-Cyano-3-trifluoromethylphenyl- carbamoyl)-2-cyclohexyl-2-hydroxy- ethyl]biphenyl-3-carboxamide 536 Example 68

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-cyclohexyl- 2-hydroxyethyl]biphenyl-3-carboxamide 550 Example 69

N-(2-Dimethylaminoethyl)-3′-[2-(4- cyano-3-trifluoromethylphenyl- carbamoyl)-2-cyclohexyl-2-hydroxy- ethyl]biphenyl-3-carboxamide 607 Example 70

3′-[2-(4-Cyano-3-trifluoromethylphenyl- carbamoyl)-2-cyclohexyl-2-hydroxy- ethyl]biphenyl-4-carboxamide 536 Example 71

3-(3′-Acetylaminobiphenyl-3-yl)-N- (4-cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxypropionamide 550 MS (ESI+) m/z (M + 1) Example 72

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-[3′-(methane- sulfonylaminomethyl)biphenyl-3-yl]- propionamide 600 Example 73

N,N-Dimethyl-3′-[2-(4-Cyano-3-tri- fluoromethylphenylcarbamoyl)-2- cyclohexyl-2-hydroxyethyl]biphenyl-4- carboxamide 564 Example 74

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(3′-methane- sulfonylbiphenyl-3-yl)propionamide 571 Example 75

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(4′-methane- sulfonylbiphenyl-3-yl)propionamide 571 Example 76

N-Cyclopropyl-3′-[2-(4-cyano-3- trifluoromethylphenylcarbamoyl)- 2-cyclohexyl-2-hydroxyethyl]- biphenyl-4-carboxamide 576 Example 77

3-(3′-Cyanobiphenyl-3-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- cyclohexyl-2-hydroxypropionamide 518 Example 78

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-[4′-(2-hydroxy- acetyl)biphenyl-3-yl]propionamide 551

EXAMPLE 79 N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-3-(3-{[(2-dimethylamino-ethyl)methylamino]methyl}phenyl)-2-hydroxypropionamide

a) 3-[2-(4-Cyano-3-trifluoromethylphenylcarbamoyl)-2-cyclohexyl-2-hydroxyethyl]-benzoic acid methyl ester

570 mg of N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-hydroxy-3-(3-iodo-phenyl)propionamide (example 26) were suspended in a glass pressure tube together with 75 mg of dichlorobis(triphenylphosphine)palladium and 0.32 ml of triethylamine in 17 ml of methanol and 1 ml of DMSO. The mixture was degassed and placed under a carbon monoxide atmosphere. The pressure tube was then closed and heated to 100° C. The mixture was stirred for 16 h and cooled, and the pressure vessel was opened. The mixture was concentrated and purified by chromatography. This afforded 293 mg (59%) of the target product.

b) N-(4-Cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-hydroxy-3-(3-hydroxymethyl-phenyl)propionamide

170 mg of the product obtained in step a) were initially charged in 6 ml of THF at RT and admixed with 0.25 ml of 1M lithium aluminum hydride solution in THF and stirred for 2 h. The reaction was ended by adding water. The mixture was extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. This afforded 156 mg (98%) of the desired product.

c) N-(4-Cyano-3-trifluoromethylphenyl)-2-cyclohexyl-3-(3-formylphenyl)-2-hydroxy-propionamide

156 mg of the product obtained in step b) were dissolved in 5 ml of dichloromethane and, at 0° C., 222 mg of Dess-Martin periodinane were added. After stirring for 2 h, the mixture was added to 1:1 sodium hydrogencarbonate solution/sodium thiosulfate solution and extracted with ethyl acetate, and the organic phases were washed with NaCl solution, dried with sodium sulfate and concentrated. This afforded 160 mg of crude product, which was converted further directly.

d) N-(4-Cyano-3-trifluoromethylphenyl)-2-cyclohexyl-3-(3-{[(2-dimethylaminoethyl)-methylamino]methyl}phenyl)-2-hydroxypropionamide

The product obtained in step c) was initially charged in 6 ml of dichloromethane, 60 μl of N,N,N′-trimethylethylenediamine were added and, after stirring at RT for 15 min, 170 mg of trisacetoxyborohydride were added in portions. After stirring for 16 h, the mixture was admixed with sodium hydrogencarbonate solution admixed (pH 9) and extracted with ethyl acetate, and the organic phases were washed with water and NaCl solution, dried with sodium sulfate and concentrated. This afforded 170 mg of crude product, which was purified by chromatography. The resulting purified racemate was separated into the enantiomers by means of chiral HPLC (Chiralcel OD-H 5μ, 250×20 mm, 99:1 hexane (0.1% DEA)/ethanol, 25 ml/min).

Example 79a: R_(t)=17.5-21.4 min

Example 79b: R_(t)=23.0-27.4 min

¹H NMR (ppm, d₆-DMSO, 400 MHz): 1.02-1.29 (m, 3H), 1.45 (m, 1H), 1.58 (m, 1H), 1.65 (m, 1H), 1.76 (m, 2H), 1.92 (m, 1H), 2.05 (m, 6H), 3.23 (m, 3H), 2.87 (d, 1H), 2.99 (d, 1H), 3.23 (m, 2H), 5.44 (s, 1H), 6.96 (m, 1H), 7.06 (m, 3H), 7.95 (d, 1H), 8.06 (dd, 1H), 8.80 (d, 1H), 9.89 (s, 1H). LCMS (ESI+): m/z=531 (M+1).

This reaction sequence can be carried out analogously beginning with the corresponding 2-iodo or 4-iodo compounds.

EXAMPLE 80 TO 95

Analogously to example 79, a multitude of different amines can be used in the reductive amination in step d). The following example compounds were prepared:

MS (ESI+) Example Structure Name m/z (M + 1) Example 80

tert-Butyl 4-{3-[2-(4-cyano-3-tri- fluoromethylphenylcarbamoyl)-2- cyclohexyl-2-hydroxyethyl]benzyl}- piperazine-1-carboxylate 615 Example 81

3-[3-(4-Acetylpiperazin-1-ylmethyl)- phenyl]-N-(4-cyano-3-trifluoromethyl- phenyl)-2-cyclohexyl-2-hydroxy- propionamide 557 Example 82

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-[3-(4-methyl- piperazin-1-ylmethyl)phenyl]propionamide 529 Example 83

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-(3-piperazin- 1-ylmethylphenyl)propionamide 515 Example 84

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-[3-(4-methane- sulfonylpiperazin-1-ylmethyl)phenyl]- propionamide 593 Example 85

Benzyl [2-(4-{3-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-cyclohexyl- 2-hydroxyethyl]benzyl}piperazin-1-yl)- ethyl]carbamate 692 Example 86

3-[3-(4-Benzoylpiperazin-1-ylmethyl)- phenyl]-N-(4-cyano-3-trifluoromethyl- phenyl)-2-cyclohexyl-2-hydroxy- propionamide 619 Example 87

3-[3-(4-Acetyl-[1,4]diazepan-1-yl- methyl)phenyl]-N-(4-cyano-3- trifluoromethylphenyl)-2-cyclohexyl- 2-hydroxypropionamide 571 Example 88

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-{3-[4-(2,2-dimethyl- propionyl)piperazin-1-ylmethyl]- phenyl}-2-hydroxypropionamide 599 Example 89

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-{3-[4-(2- morpholin-4-yl-2-oxoethyl)piperazin- 1-ylmethyl]phenyl}propionamide 642 Example 90

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-{3-[4-(2- oxo-2-pyrrolidin-1-ylethyl)piperazin- 1-ylmethyl]phenyl}propionamide 626 Example 91

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-{3-[4-(2-dimethylamino- ethyl)piperazin-1-ylmethyl]phenyl}- 2-hydroxypropionamide 586 Example 92

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-{3-[(2-dimethylamino- ethylamino)methyl]phenyl}-2-hydroxy- propionamide 517 Example 93

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-3-(3-{[(3-dimethylamino- propyl)methylamino]methyl}phenyl)- 2-hydroxypropionamide 545 Example 94

N-(4-Cyano-3-trifluoromethylphenyl)- 2-cyclohexyl-2-hydroxy-3-{3-[(2-piperidin- 1-ylethylamino)methyl]phenyl}propionamide 557 Example 95

3-{3-[4-(2-Benzyloxyacetyl)piperazin- 1-ylmethyl]phenyl}-N-(4-cyano-3-tri- fluoromethylphenyl)-2-cyclohexyl-2- hydroxypropionamide 663

EXAMPLE 96 3-[3-(4-Benzoylpiperazine-1-carbonyl)-phenyl]-N-(4-cyano-3-trifluoromethyl-phenyl)-2-cyclohexyl-2-hydroxypropionamide

a) 250 mg of the methyl ester obtained in example 79a) were dissolved in 5 ml of 1:1 THF/water and 125 mg of LiOH were added. The mixture was stirred at RT for 16 h, water was added, and the mixture was adjusted to pH 4 with 2M HCl, extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. The crude product was recrystallized from dichloromethane and converted further directly.

b) 50 mg of the acid obtained in a), 30 mg of benzoylpiperazine and 0.05 ml of triethylamine were dissolved in 6 ml of DMF, and 46 mg of the coupling reagent HATU were added. The mixture was stirred at RT for 16 h, water was added, and the mixture was extracted with ethyl acetate, washed with NaCl solution, dried with sodium sulfate and concentrated. The crude product was chromatographed on amino phase. This afforded 20 mg of the desired product.

LCMS: ES+: m/z=633 (M+1), ES−: m/z=631 (M−1)

Analogously, further examples can be prepared using various amine components.

EXAMPLE 97 N-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-2-cyclohexyl-2-hydroxy-3-phenyl-propionamide

a) 5-Nitro-1-methyl-1H-pyrrole-2-carbonitrile

1.2 g of 1-methyl-1H-pyrrole-2-carbonitrile were dissolved in 7 ml of acetic anhydride. At 0° C., a mixture of 1 ml of fuming nitric acid and 2 ml of acetic anhydride was added dropwise at such a rate that the internal temperature did not rise above 1° C. After 2 h, the mixture was added to 25 ml of ice-water, extracted with diethyl ether and ethyl acetate, dried with sodium sulfate and concentrated. The crude product was purified by chromatography. This afforded 170 mg of the desired isomer: ¹H NMR (ppm, d₆-DMSO, 400 MHz): 3.98 (s, 3H), 7.12 (d, 1H), 7.27 (d, 1H); and 260 mg of 4-nitro-1-methyl-1H-pyrrole-2-carbonitrile ¹H NMR (ppm, d₆-DMSO, 400 MHz): 3.79 (s, 3H), 7.67 (s, 1H), 8.31 (s, 1H).

b) 5-Amino-1-methyl-1H-pyrrole-2-carbonitrile

200 mg of 5-nitro-1-methyl-1H-pyrrole-2-carbonitrile were dissolved in 6 ml of ethyl acetate, 140 mg of palladium (10% on activated carbon) were added and hydrogenation was effected at RT and 1 atm of hydrogen pressure. The catalyst was filtered off and the solution was concentrated. This afforded 160 mg of the desired product. ¹H NMR (ppm, CDCl₃, 400 MHz): 2.85 (s br, 2H), 3.65 (s, 3H), 6.29 (d, 1H), 6.35 (d, 1H);

c) N-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-2-cyclohexyl-2-oxoacetamide

116 mg of cyclohexyloxoacetic acid and 90 mg of 5-amino-1-methyl-1H-pyrrole-2-carbonitrile were converted analogously to the preparation of N-(3-chloro-4-cyanophenyl)-2-oxo-2-cyclohexylacetamide (see above) to N-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-cyclohexyl-2-oxoacetamide. Yield 125 mg (65%).

d) N-(5-Cyano-1-methyl-1H-pyrrol-2-yl)-2-cyclohexyl-2-hydroxy-3-phenyl-propionamide

107 mg of the keto amide obtained in step c) were reacted analogously to example 20 with benzylmagnesium chloride. This afforded 97 mg (90%) of the desired product. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.10-1.36 (m, 5H), 1.65-1.86 (m, 5H), 1.99 (m, 1H), 2.87 (d, 1H), 3.42 (d, 1H), 3.73 (s, 3H), 6.42 (m, 1H), 7.16 (m, 2H), 7.26 (m, 3H), 7.41 (m, 1H), 8.13 (s, 1H).

EXAMPLE 98 N-(5-Cyano-1-methyl-1H-pyrrol-3-yl)-2-cyclohexyl-2-hydroxy-3-phenylpropionamide

Analogously to example 97, the sequence can also be carried out with the 4-nitro-1-methyl-1H-pyrrole-2-carbonitrile obtained in step a) of example 97. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.10-1.39 (m, 5H), 1.60-2.03 (m, 5H), 2.23 (m, 1H), 2.85 (d, 1H), 3.35 (d, 1H), 3.74 (s, 3H), 5.95 (m, 1H), 6.70 (d, 1H), 6.80 (m, 3H), 7.21 (m, 1H), 7.26 (m, 1H), 8.10 (s, 1H).

EXAMPLE 99 tert-Butyl rac-4-[1-(4-cyano-3-trifluoromethyl phenylcarbamoyl)-1-hydroxy-2-phenylethyl]piperidine-1-carboxylate

a) tert-Butyl 4-(acetoxyethoxycarbonylmethylene)piperidine-1-carboxylate

26.15 g of ethyl acetoxy(diethoxyphosphoryl)acetate were initially charged in 130 ml of THF, 3.93 g of lithium chloride were added and the mixture was cooled to 0° C. 12 ml of N,N,N′,N′-tetramethylguanidine were added dropwise and the mixture was stirred for 15 min. Then 14 g of 1-(tert-butyloxycarbonyl)-4-piperidinone, dissolved in 60 ml of THF, were added dropwise. The mixture was allowed to come to room temperature and was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, and the phases were separated and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. The residue was chromatographed on silica gel. This afforded 22.5 g of the desired intermediate as a colorless oil. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.27 (t, 3H), 1.45 (s, 9H), 2.20 (s, 3H), 2.32 (dt, 2H), 2.91 (dt, 2H), 3.47 (m, 4H), 4.20 (q, 2H).

b) tert-Butyl 4-oxalylpiperidine-1-carboxylate

22.5 g of tert-butyl 4-(acetoxyethoxycarbonylmethylene)piperidine-1-carboxylate were added to 140 ml of 1M sodium hydroxide solution in 2:1 ethanol/water. The mixture was left to stir at room temperature for 30 min, then diluted with 1.4 l of cold water, acidified with hydrochloric acid (pH 3-4), extracted with ethyl acetate and with dichloromethane/methanol, then acidified to pH 2-3 and extracted again with dichloromethane/methanol. The combined organic phases were dried with sodium sulfate and concentrated. This afforded 16.9 g of tert-butyl 4-oxalylpiperidine-1-carboxylate as a colorless solid. LCMS: m/z (ES−)=256 (M−1).

c) tert-Butyl 4-(4-cyano-3-trifluoromethylphenylaminooxalyl)piperidine-1-carboxylate

16.9 g of tert-butyl 4-oxalylpiperidine-1-carboxylate were initially charged in 500 ml of dimethylacetamide and 8.6 ml of thionyl chloride were added dropwise at 0° C. After 30 min, 12.23 g of 5-amino-2-cyanobenzotrifluoride were added and the mixture was stirred at RT for 18 h. The mixture was added slowly and with vigorous stirring to 1.8 l of water and stirred for a further 2.5 h. The crystals were filtered off and dried in a vacuum drying cabinet. This afforded 21.5 g of the desired keto amide. ¹H NMR (ppm, d₆-DMSO, 400 MHz): 1.30 (m, 4H), 1.36 (s, 9H), 1.82 (m, 2H), 3.45 (m, 1H), 3.92 (m, 2H), 8.13 (d, 1H), 8.24 (dd, 1H), 8.48 (d, 1H), 11.22 (s, 1H).

d) tert-Butyl rac-4-[1-(4-cyano-3-trifluoromethylphenylcarbamoyl)-1-hydroxy-2-phenyl-ethyl]piperidine-1-carboxylate

4.2 g of tert-Butyl 4-(4-cyano-3-trifluoromethylphenylaminooxalyl)piperidine-1-carboxylate were initially charged in 129 ml of THF under Ar and, at 0° C., 14 ml of a 2 molar benzylmagnesium bromide solution in THF were added dropwise. The mixture was allowed to thaw to RT and stirred for a further 14 h. The reaction was ended by adding ammonium chloride solution. The mixture was partitioned between ethyl acetate and water, and the phases were separated and extracted with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. Recrystallization from dichloromethane afforded the desired product in approx. 70% yield. ¹H NMR (ppm, CDCl₃, 400 MHz): 1.45 (s, 9H), 1.57 (m, 2H), 1.91 (m, 1H), 2.29 (m, 1H), 2.70 (m, 2H), 2.88 (d, 1H), 3.48 (d, 1H), 4.22 (m, 2H), 4.71 (s, 1H), 7.15 (m, 3H), 7.28 (m, 2H), 7.74 (d, 1H), 7.79 (dd, 1H), 7.88 (d, 1H), 8.63 (s, 1H).

EXAMPLE 100 N-(4-Cyano-3-trifluoromethyl phenyl)-2-hydroxy-3-phenyl-2-piperidin-4-yl-propionamide

5 g of tert-butyl rac-4-[1-(4-cyano-3-trifluoromethylphenylcarbamoyl)-1-hydroxy-2-phenylethyl]piperidine-1-carboxylate were dissolved in 120 ml of dichloromethane, 20 ml of trifluoroacetic acid were added dropwise and the mixture was stirred for 16 h. The mixture was added to sodium carbonate solution/ice, adjusted to pH 8 with potassium carbonate and extracted with dichloromethane. The organic phases were dried with sodium sulfate and concentrated. This afforded 4.8 g of the racemic product, which was separated into the enantiomers by means of chiral HPLC (Chiralcel OD-H 5μ, 250×20 mm, 9:1 hexane/ethanol).

Example 100a: R_(t)=9.4-11.4 min; [α]^(D) ₂₀=+70.50 (MeOH, c=0.46)

Example 100b: R_(t)=12.6-14.3 min; [α]^(D) ₂₀=−74.0° (MeOH, c=0.47)

¹H NMR (ppm, d₆-DMSO, 400 MHz): 1.57 (m, 3H), 2.00 (m, 2H), 1.81 (m, 2H), 2.91 (d, 1H), 3.04 (d, 1H), 3.30 (m, 2H), 5.89 (s, 1H), 7.13 (m, 5H), 8.00 (d, 1H), 8.07 (dd, 1H), 8.27 (d, 1H), 10.02 (s, 1H).

EXAMPLE 101 2-(1-Benzoylpiperidin-4-yl)-N-(4-cyano-3-trifluoromethyl phenyl)-2-hydroxy-3-phenylpropionamide

180 mg of rac-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-phenyl-2-piperidin-4-ylpropionamide were initially charged at 0° C. in 9 ml of dichloromethane and admixed with 0.12 ml of triethylamine, and 0.06 ml of benzoyl chloride was added dropwise. The mixture was allowed to come to RT and was stirred for approx. 14 h. The reaction was ended by adding sodium hydrogencarbonate solution, the phases were separated, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried with sodium sulfate and concentrated. The crude product was recrystallized from diisopropyl ether/dichloromethane/hexane. The resulting 90 mg of racemate were separated by means of chiral HPLC into the enantiomers (Chiralpak IA 5μ 250×20 mm, 8:2 hexane/ethanol, 25 ml/min).

Example 101a: R_(t)=9.9-11.4 min

Example 101b: R_(t)=11.6-14.2 min

¹H NMR (ppm, CDCl₃, 400 MHz): 1.58 (m, 3H), 2.00 (m, 1H), 2.25 (m, 1H), 2.90 (d, 1H), 2.90 (m, 2H), 3.30 (m, 1H), 3.35 (d, 1H), 3.88 (m, 1H), 7.14 (m, 2H), 7.22 (m, 3H), 7.37 (m, 5H), 7.70 (m, 2H), 7.80 (s, 1H), 8.61 (s, 1H).

Analogously, by reaction of N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-phenyl-2-piperidin-4-ylpropionamide with the appropriate carbonyl chloride or sulfonyl chloride, the following compound were prepared and, where appropriate, separated into the enantiomers:

MS (ESI+) Example Structure Name m/z (M + 1) Example 102

2-(1-Acetylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenylpropionamide 460 Example 103

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-(1-methanesulfonyl- piperidin-4-yl)-3-phenylpropionamide 496 Example 104

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(2,2-dimethylpropionyl)- piperidin-4-yl]-2-hydroxy-3-phenyl- propionamide 502 Example 105

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-(1-methylpiperidin-4-yl)- 3-phenylpropionamide 432 Example 106

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenyl-2-(1-phenylacetyl- piperidin-4-yl)propionamide 536 Example 107

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(2,5-dimethyl-2H-pyrazole-3- carbonyl)piperidin-4-yl]-2-hydroxy- 3-phenylpropionamide 540 Example 108

N-(4-Cyano-3-trifluoromethylphenyl)- 2-(1-cyclopropanecarbonylpiperidin- 4-yl)-2-hydroxy-3-phenylpropion amide 486 Example 109

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(3-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxy-3-phenyl- propionamide 576 Example 110

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(3-methoxybenzene- sulfonyl)piperidin-4-yl]-3-phenyl- propionamide 588 Example 111

2-[1-(3-Chlorobenzenesulfonyl)- piperidin-4-yl]-N-(4-cyano-3-trifluoro- methylphenyl)-2-hydroxy-3-phenyl- propionamide 592 Example 112

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxy-3-phenyl- propionamide 576 Example 113

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(isoxazole-5- carbonyl)piperidin-4-yl]-3-phenyl- propionamide 513 Example 114

N-(4-Cyano-3-trifluoromethylphenyl)- 2-{1-[2-(4-fluorophenyl)acetyl]- piperidin-4-yl}-2-hydroxy-3-phenyl- propionamide 554 Example 115

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(5-methylisoxazole- 4-sulfonyl)piperidin-4-yl]-3-phenyl- propionamide 563 Example 116

2-(1-Benzenesulfonylpiperidin-4-yl)- N-(4-cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenylpropionamide 558 Example 117

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenyl-2-[1-(pyrazine- 2-carbonyl)piperidin-4-yl]propion- amide 524 Example 118

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(2,2-difluoro-2-phenylacetyl)- piperidin-4-yl]-2-hydroxy-3-phenyl- propionamide 572 Example 119

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(5-methylisoxazole- 4-carbonyl)piperidin-4-yl]-3-phenyl- propionamide 527 Example 120

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(1-methyl-1H-imid- azole-4-sulfonyl)piperidin-4-yl]-3- phenylpropionamide 562 Example 121

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(3,5-dimethylisoxazole-4- carbonyl)piperidin-4-yl]-2-hydroxy-3- phenylpropionamide 541 Example 122

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenyl-2-[1-(thiazole- 2-carbonyl)piperidin-4-yl]propion- amide 529 Example 123

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenyl-2-[1-([1,2,3]- thiadiazole-4-carbonyl)piperidin-4- yl]propionamide 530 Example 124

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-[1-(3-methyl-3H-imid- azole-4-carbonyl)piperidin-4-yl]-3- phenylpropionamide 526 Example 125

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-phenyl-2-(1-trifluoro- methanesulfonylpiperidin-4-yl) propionamide 550 Example 126

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(2-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxy-3-phenyl- propionamide 576

EXAMPLE 127 tert-Butyl 4-[1-(4-cyano-3-trifluoromethyl phenylcarbamoyl)-1-hydroxy-2-(3-iodophenyl)ethyl]piperidine-1-carboxylate

3.5 g of tert-butyl 4-(4-cyano-3-trifluoromethylphenylaminooxalyl)piperidine-1-carboxylate (for preparation see above) were dissolved under Ar at −75° C. in 150 ml of THF, then 50 ml of a 0.5 M solution of 3-iodobenzylzinc bromide in THF were added dropwise and the mixture was thawed overnight. The reaction was ended with ammonium chloride solution and diluted with ethyl acetate, the phases were separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were washed with NaCl solution and dried with sodium sulfate. The crude product was purified by chromatography. This afforded 2.32 g of a pale yellowish solid, which was separated into the enantiomers by means of chiral HPLC (Chiralpak IA 5μ, 250×30 mm, 9:1 hexane/ethanol, 40 ml/min)

Example 127a: R_(t)=8.6-9.5 min; [α]^(D) ₂₀=−38.0° (MeOH, c=1.03)

Example 127b: R_(t)=9.6-10.7 min; [α]^(D) ₂₀=+19.4° (MeOH, c=0.48)

¹H NMR (ppm, d₆-DMSO, 400 MHz): 1.35 (s, 9H), 1.38 (m, 3H), 1.80 (m, 1H), 1.95 (m, 1H), 2.58 (m, 2H), 2.83 (d, 1H), 2.97 (d, 1H), 3.98 (m, 2H), 5.72 (s, 1H), 6.93 (m, 1H), 7.15 (d, 1H), 7.40 (d, 1H), 7.54 (s, 1H), 7.99 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 9.97 (s, 1H).

Analogously, by reaction with 2-iodobenzylzinc bromide or 4-iodobenzylzinc bromide, the corresponding ortho- and para-iodo compounds can be obtained:

EXAMPLE 130 N-(4-Cyano-3-trifluoromethyl phenyl)-2-hydroxy-3-(3-iodophenyl)-2-piperidin-4-ylpropionamide

The reaction was effected analogously to example 100. One hour of reaction time was sufficient.

LCMS: m/z=544 (ES+, M+1); 542 (ES−, M−1)

The corresponding 2-iodo and 4-iodo compounds are obtained analogously.

EXAMPLE 131 2-(1-Benzoylpiperidin-4-yl)-N-(4-cyano-3-trifluoromethyl phenyl)-2-hydroxy-3-(3-iodophenyl)propionamide

The reaction was effected analogously to example 101. 1.77 g of amine afforded 1.9 g (90%) of the desired product. 1.1 equivalents of benzoyl chloride were used.

LCMS: m/z=648 (ES+, M+1); 646 (ES−, M−1)

EXAMPLE 132 3′-[2-(1-Benzoylpiperidin-4-yl)-2-(4-cyano-3-trifluoromethyl phenylcarbamoyl)-2-hydroxyethyl]biphenyl-3-carboxamide

100 mg of 2-(1-benzoylpiperidin-4-yl)-N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-(3-iodophenyl)propionamide and 26 mg of (3-aminocarbonylphenyl)boronic acid were initially charged in 2 ml of 1:1 toluene/ethanol, admixed with 0.15 ml of 2M sodium carbonate solution and 18 mg of tetrakis(triphenylphosphine)palladium and irradiated in a microwave at 150 W/120° C. for 30 min. Thereafter, the mixture was partitioned between water and ethyl acetate, filtered together and then the phases were separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were washed with sat. NaCl solution, dried with sodium sulfate and concentrated. The crude product was purified by chromatography. This afforded 37 mg (38%) of the desired product as a colorless solid.

¹H NMR (ppm, CDCl₃, 400 MHz): 1.45-1.70 (m, 3H), 1.83-2.02 (m, 1H), 2.29-2.39 (m, 1H), 2.73-2.87 (m, 1H), 2.98 (d, 1H), 2.96-3.09 (m, 1H), 3.18 (d, 1H), 3.75-3.90 (m, 1H), 4.72-4.89 (m, 1H), 6.21 (s br, 1H), 6.77 (s br, 1H), 7.12-7.20 (m, 2H), 7.36 (m, 5H), 7.39-7.44 (m, 1H), 7.48-7.72 (m, 6H), 7.78 (s, 1H), 8.05 (s, 1H), 8.85 (s, 1H).

LCMS: m/z=641 (ES+, M+1); 639 (ES−, M−1)

By reaction of N-(4-cyano-3-trifluoromethylphenyl)-2-hydroxy-3-(3-iodophenyl)-2-piperidin-4-ylpropionamide (example 130) with a multitude of carbonyl chlorides and sulfonyl chlorides, it was possible using the process described in example 131 to prepare appropriate starting compounds for Suzuki reactions, which were converted analogously to example 132. Alternatively, a changeover of the reaction sequence was also possible. In this case, the Suzuki reaction (analogously to example 132) was carried out on the Boc-protected intermediate (analogously to example 127), which was followed by Boc-deprotection (analogously to example 130) and acylation or sulfonamide formation analogously to example 131. The enantiomers, which were pure in each case, were obtained by preparative chiral HPLC of the end compound or by performing the reaction sequence with material already separated at the stage of example 127.

The following further example compounds were prepared.

MS (ESI+) m/z Example Structure Name (M + 1) Example 133

tert-Butyl 4-[2-(4′-acetylamino- biphenyl-3-yl)-1-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-1-hydroxy- ethyl]piperidine-1-carboxylate 651 Example 134

tert-Butyl 4-[1-(4-cyano-3-trifluoromethyl- phenylcarbamoyl)-1-hydroxy-2-(4′- methylcarbamoylbiphenyl-3-yl)ethyl]- piperidine-1-carboxylate 651 Example 135

tert-Butyl 4-[1-(4-Cyano-3-trifluoro- methylphenylcarbamoyl)-1-hydroxy- 2-(4′-methylsulfamoyl-biphenyl-3-yl)- ethyl]piperidine-1-carboxylate 687 Example 136

tert-Butyl 4-[1-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-(4′- dimethylsulfamoylbiphenyl-3-yl)- 1-hydroxyethyl]piperidin-1-carboxylate 701 Example 137

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-hydroxy- 2-(1-methanesulfonyl-piperidin-4-yl)- ethyl]biphenyl-4-carboxamide 629 Example 138

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-(1-methanesulfonylpiperidin- 4-yl)-3-(4′-methylsulfamoylbiphenyl- 3-yl)propionamide 665 Example 139

N-(4-Cyano-3-trifluoromethylphenyl)- 3-(4′-dimethylsulfamoylbiphenyl- 3-yl)-2-hydroxy-2-(1-methanesulfonyl- piperidin-4-yl)propionamide 679 Example 140

tert-Butyl 4-{1-(4-cyano-3-trifluoromethyl- phenylcarbamoyl)-1-hydroxy-2-(4′-(5- hydroxy-5-trifluoromethyl-4,5-dihydro- isoxazol-3-yl)biphenyl-3- yl]ethyl}piperidine-1-carboxylate 747 Example 141

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-[4′-(5-hydroxy-5-trifluoro- methyl-4,5-dihydroisoxazol-3-yl)- biphenyl-3-yl]-2-piperidin-4-yl- propionamide 647 Example 142

tert-Butyl 4-{1-(4-cyano-3-trifluoromethyl- phenylcarbamoyl)-1-hydroxy-2-[4′- (methane-sulfonylaminomethyl)biphenyl- 3-yl]ethyl}-piperidine-1-carboxylate 701 Example 143

3-(4′-Acetylaminobiphenyl-3-yl)-N- (4-cyano-3-trifluoromethylphenyl)- 2-hydroxy-2-(1-methanesulfonyl- piperidin-4-yl)propionamide 629 Example 144

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[4′-(5-hydroxy-5-trifluoro- methyl-4,5-dihydroisoxazol-3-yl)- biphenyl-3-yl]propionamide 751 Example 145

3-(4′-Acetylaminobiphenyl-3-yl)-2- (1-benzoylpiperidin-4-yl)-N-(4-cyano- 3-trifluoromethylphenyl)-2-hydroxy- propionamide 655 Example 146

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-3- (4′-dimethylsulfamoylbiphenyl-3- yl)-2-hydroxypropionamide 705 Example 147

N-Methyl-3′-[2-(1-benzoylpiperidin- 4-yl)-2-(4-cyano-3-trifluormethyl- phenylcarbamoyl)-2-hydroxyethyl]- biphenyl-4-carboxamide 655 Example 148

3′-[2-(1-Benzoylpiperidin-4-yl)-2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]biphenyl- 4-carboxamide 641 Example 149

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-(4-methanesulfonylamino- biphenyl-3-yl)propionamide 691 Example 150

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[4′-(methanesulfonylamino- methyl)biphenyl-3-yl]propionamide 705 Example 151

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-(4′-methylsulfamoyl- biphenyl-3-yl)propionamide 691 Example 152

N-(4-Cyano-3-trifluoromethylphenyl)- 2-hydroxy-3-[4′-(5-hydroxy-5-trifluoro- methyl-4,5-dihydroisoxazol-3-yl)- biphenyl-3-yl]-2-(1-methanesulfonyl- piperidin-4-yl)propionamide 725 Example 153

3′-[2-(1-Benzoylpiperidin-4-yl)-2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]- biphenyl-3-carboxamide 641 Example 154

3-(3′-Acetylaminobiphenyl-3-yl)-2- (1-benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxypropionamide 655 Example 155

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[3′-(methanesulfonylamino- methyl)biphenyl-3-yl]propionamide 705 Example 156

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-3- (3′-dimethylsulfamoylbiphenyl-3- yl)-2-hydroxypropionamide 705 Example 157

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-(3′-methanesulfonylamino- biphenyl-3-yl)propionamide 691 Example 158

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-(3′-methylsulfamoyl- biphenyl-3-yl)propionamide 691 Example 159

N-Methyl-3′-[2-(1-benzoylpiperidin-4-yl)- 2-(4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]biphenyl- 3-carboxamide 655 Example 160

3′-[2-(1-Benzoylpiperidin-4-yl)-2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]- biphenyl-3-carboxylic acid 642 Example 161

N-(2-Dimethylaminoethyl)-3′-[2- (1-benzoylpiperidin-4-yl)-2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]- biphenyl-3-carboxamide 712 Example 162

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[3′-(morpholine-4-carbonyl)- biphenyl-3-yl]propionamide 711 Example 163

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[3′-(piperazine-1-carbonyl)- biphenyl-3-yl]propionamide 710 Example 164

N-(2-Dimethylaminoethyl)-3′-[2- (1-benzoylpiperidin-4-yl)-2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-hydroxyethyl]biphenyl- 4-carboxamide 712 Example 165

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[4′-(piperazine-1-carbonyl)- biphenyl-3-yl]propionamide 710 Example 166

2-(1-Benzoylpiperidin-4-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- hydroxy-3-[4′-(morpholine-4-carbonyl)- biphenyl-3-yl]propionamide 711 Example 167

tert-Butyl 4-[1-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-1-hydroxy- 2-(3′-methylcarbamoylbiphenyl-3- yl)ethyl]piperidine-1-carboxylate 651 Example 168

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-hydroxy- 2-piperidin-4-ylethyl]biphenyl- 3-carboxamide 551 Example 169

N-Methyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-[1-(3-fluoro- benzenesulfonyl)-piperidin-4-yl]-2- hydroxyethyl}biphenyl-3-carboxamide 709 Example 170

N-Methyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)-piperidin-4-yl]-2- hydroxyethyl}biphenyl-3-carboxamide 709 Example 171

3′-{2-(4-Cyano-3-trifluoromethyl- phenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)piperidin-4-yl]-2- hydroxyethyl}biphenyl-4- carboxamide 695 Example 172

3′-{2-(4-Cyano-3-trifluoromethyl- phenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)piperidin-4-yl]-2- hydroxyethyl}biphenyl-3- carboxamide 695 Example 173

N-(4-Cyano-3-trifluoromethyl- phenyl)-2-[1-(4-fluorobenzene- sulfonyl)piperidin-4-yl]-2- hydroxy-3-(3′-sulfamoylbiphenyl- 3-yl)propionamide 731 Example 174

3-(3′-Cyanobiphenyl-3-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- [1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxypropionamide 677 Example 175

3-(3′-Acetylbiphenyl-3-yl)-N-(4- cyano-3-trifluoromethylphenyl)-2- [1-(4-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxypropionamide 694 Example 176

N-(4-Cyano-3-trifluoromethyl- phenyl)-2-[1-(4-fluorobenzene- sulfonyl)piperidin-4-yl]-3-(3′- formylbiphenyl-3-yl)-2- hydroxypropionamide 680 Example 177

3′-{2-(4-Cyano-3-trifluoromethyl- phenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)-piperidin-4-yl]-2- hydroxyethyl}biphenyl-3-carboxylic acid 696 Example 178

N-(2-Dimethylaminoethyl)-3′-{2- (4-cyano-3-trifluoromethylphenyl- carbamoyl)-2-[1-(4-fluorobenzene- sulfonyl)piperidin-4-yl]-2-hydroxy- ethyl}biphenyl-3-carboxamide 766 Example 179

N-(2-Methoxyethyl)-3′-{2-(4-cyano- 3-trifluoromethylphenylcarbamoyl)-2- [1-(4-fluorobenzenesulfonyl)-piperidin- 4-yl]-2-hydroxyethyl}biphenyl-3- carboxamide 753 Example 180

N-Cyclopropyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)piperidin-4-yl]-2- hydroxyethyl}biphenyl-3-carboxamide 735 Example 181

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxy-3-(3′- methanesulfonylaminobiphenyl-3-yl)- propanamide 745 Example 182

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-[3′-(5-hydroxy-5- trifluoromethyl-4,5-dihydroisoxazol-3- yl)biphenyl-3-yl]propionamide 805 Example 183

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-[3′-(morpholine-4- carbonyl)biphenyl-3-yl]propionamide 765 Example 184

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-(3′-morpholin-4- ylmethylbiphenyl-3-yl)propionamide 751 Example 185

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-[3′-(4-methylpiperazin- 1-ylmethyl)biphenyl-3-yl]propionamide 764 Example 186

N-(4-Cyano-3-trifluoromethylphenyl)- 3-(3′-dimethylsulfamoylbiphenyl- 3-yl)-2-[1-(4-fluorobenzenesulfonyl)- piperidin-4-yl]-2-hydroxypropionamide 759 Example 187

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-(3′-methylsulfamoyl- biphenyl-3-yl)propionamide 745 Example 188

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-(3-pyridin-3-yl- phenyl)propionamide 653 Example 189

N,N-Dimethyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-[1-(4-fluoro- benzenesulfonyl)piperidin-4-yl]-2- hydroxyethyl}biphenyl-3-carboxamide 723 Example 190

3-Biphenyl-3-yl-N-(4-cyano-3- trifluoromethylphenyl)-2-[1-(4- fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxypropionamide 652 Example 191

N-(4-Cyano-3-trifluoromethylphenyl)- 2-[1-(4-fluorobenzenesulfonyl)piperidin- 4-yl]-2-hydroxy-3-(3-pyridin-4-yl- phenyl)propionamide 653 Example 192

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-hydroxy- 2-(1-phenylacetylpiperidin-4-yl)ethyl]- biphenyl-3-carboxamide 669 Example 193

N-Methyl-3′-[2-(1-benzenesulfonyl- piperidin-4-yl)-2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-hydroxy- ethyl]biphenyl-3-carboxamide 691 Example 194

N-Methyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-[1-(2,5- dimethyl-2H-pyrazole-3-carbonyl)- piperidin-4-yl]-2-hydroxyethyl}- biphenyl-3-carboxamide 673 Example 195

N-Methyl-3′-[2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-(1-cyclo- propanecarbonylpiperidin-4-yl)-2- hydroxyethyl]biphenyl-3-carboxamide 619 Example 196

N-Methyl-3′-{2-(4-cyano-3-trifluoro- methylphenylcarbamoyl)-2-hydroxy- 2-[1-(pyridine-4-carbonyl)piperidin- 4-yl]ethyl}biphenyl-3-carboxamide 565 Example 197

3′-{2-(4-Cyano-3-trifluoromethyl- phenylcarbamoyl)-2-hydroxy-2- [1-(isoxazole-5-carbonyl)piperidin- 4-yl]ethyl}biphenyl-3-carboxamide 632

EXAMPLE 198 N-(4-Cyano-3-trifluoromethyl phenyl)-2-(4,4-difluorocyclohexyl)-2-hydroxy-3-phenylpropionamide

The compound was prepared analogously to example 99, beginning with 4,4-difluoro-cyclohexanone and separated into the enantiomers by means of chiral HPLC (Chiralpak AD-H 5μ, 250×20 mm, 8:2 hexane/ethanol, 25 ml/min).

Example 198a: R_(t)=5.1-6.1 min

Example 198b: R_(t)=7.1-8.1 min

¹H NMR (ppm, CDCl₃, 400 MHz): 1.57-2.25 (m, 9H), 2.90 (d, 1H), 3.48 (d, 1H), 7.16 (m, 2H), 7.29 (m, 3H), 7.75 (d, 1H), 7.80 (dd, 1H), 7.88 (d, 1H), 8.63 (s, 1H).

EXAMPLE 199 N-(4-Cyano-3-trifluoromethyl phenyl)-2-hydroxy-3-phenyl-2-(4-trifluoromethyl-cyclohexyl)propionamide

The compound was prepared analogously to example 99, beginning with 4-trifluoromethylcyclohexanone and separated into the isomers by means of chiral HPLC (Chiralpak IA 5μ, 250×20 mm, 9:1 hexane/ethanol, 25 ml/min). LCMS (ESI+) m/z=485 (M+1).

EXAMPLE 200 N-(4-Cyano-3-trifluoromethyl phenyl)-2-cyclohexyl-2-hydroxy-3-(3-hydroxy-phenyl)propionamide

300 mg of N-(4-cyano-3-trifluoromethylphenyl)-2-cyclohexyl-2-hydroxy-3-(3-methoxy-phenyl)propionamide (example 24) were dissolved in 20 ml of dichloromethane and, at −10° C., 2 ml of tribromoborane were added dropwise. The mixture was left to stir at RT for 16 h, then the mixture was added to ice-water, extracted with ethyl acetate, washed with water and NaCl solution, dried with sodium sulfate and concentrated. The crude product was purified by chromatography (yield: 150 mg, 52%). The racemate was separated into the enantiomers by means of chiral HPLC (Chiralpak IA 5μ, 250×20 mm, 85:15 hexane/ethanol, 25 ml/min).

Example 200a: R_(t)=7.6-8.8 min; [α]^(D) ₂₀=+116.5° (CHCl₃, c=0.34)

Example 200b: R_(t)=9.9-11.5 min; [α]^(D) ₂₀=−122.5° (CHCl₃, c=0.43)

¹H NMR (ppm, CDCl₃, 400 MHz): 1.14 (m, 2H), 1.29 (m, 3H), 1.68 (m, 2H), 1.78 (m, 1H), 1.88 (m, 2H), 1.99 (m, 1H), 2.85 (d, 1H), 3.37 (d, 1H), 5.14 (s, 1H), 6.69 (m, 3H), 7.13 (dd, 1H), 7.78 (d, 1H), 7.82 (dd, 1H), 7.89 (d, 1H), 8.69 (s, 1H).

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 07076093.9, filed Dec. 14, 2007, are incorporated by reference herein.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. 

1. Compounds of the general formula (I)

in which A is hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl radical which is optionally mono- or polysubstituted identically or differently by Z, or else is Z itself, where Z is defined as follows: cyano, halogen, hydroxyl, nitro, —C(O)R^(b), C(O)CH₂R^(b), —C(O)CF₂R^(b), CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), —C═NOR^(b), —NR^(c)R^(d), PO₃(R^(b))₂, —NR^(e)COR^(b), —NR^(e)CSR^(b), —NR^(e)S(O)R^(b), —NR^(e)S(O)₂R^(b), NR^(e)CONR^(c)R^(d), —NR^(e)COOR^(b), —NR^(e)C(NH)NR^(c)R^(d), —NR^(e)CSNR^(c)R^(d), —NR^(e)S(O)NR^(c)R^(d), —NR^(e)S(O)₂NR^(c)R^(d), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b), —S(O)₂CH₂R^(b), —S(O)₂CF₂R^(b), —SO₂OR^(b), —CSNR^(c)R^(d), —CR^(b)(OH)—R^(b) where  R^(b) is hydrogen, a C₁-C₆-alkyl, hydroxy-C₁-C₃-alkyl, C₁-C₃-alkoxy-C₁-C₃-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, —(CH₂)_(p)C(O)₂H, —(CH₂)_(p)C(O)₂C₁-C₃-alkyl, a 5- to 6-membered cycloalkyl or heterocycloalkyl radical which is optionally mono- or disubstituted by a halogen, a C₁-C₃-alkyl, C₁-C₃-alkoxy radical or a COOR^(b) radical and has 1, 2 or 3 heteroatoms or a phenyl or 3-12-membered heteroaryl radical which is optionally mono- or disubstituted by a halogen, a C₁-C₃-alkyl, C₁-C₃-alkoxy radical or a COOR^(b) radical and has 1, 2 or 3 heteroatoms, or a —(CH₂)_(p)—C₆-C₁₂-aryl radical which is optionally mono- or disubstituted by a halogen, a C₁-C₃-alkyl, C₁-C₃-alkoxy radical or a COOR^(b) radical or a partly or fully fluorinated C₁-C₃-fluoroalkyl radical  and  R^(c) and R^(d) are each independently hydrogen, a C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl radical or a 5- to 12-membered heteroaryl radical optionally substituted by W, a C(O)R^(b) group with the definition of R^(b) specified above —S(O)₂C₁-C₃-alkyl, —C(O)C₁-C₃-alkyl or a hydroxyl group, or together including the nitrogen form a 3- to 7-membered ring which is optionally mono- or disubstituted by a trifluoromethyl and/or hydroxyl group and which is optionally extended by O, S or NR^(f) where W is —NR^(g)R^(h) where R^(g) is hydrogen or C₁-C₃-alkyl and R^(h) is hydrogen or C₁-C₃-alkyl or R^(g) and R^(h) together including the nitrogen form a 3- to 7-membered ring which is optionally extended by O, S or NR^(f) and R^(f) is hydrogen, C₁-C₃-alkyl, C₁-C₃-acyl, C₁-C₃-alkylsulphonyl or C₁-C₃-alkoxycarbonyl, and where, when R^(c) is a hydroxyl group, R^(d) can only be hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl which is optionally substituted by W, and vice versa, and also R^(e) is hydrogen, C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl or C₆-C₁₂-aryl which is optionally substituted by W, or A is a C₃-C₁₀-cycloalkyl radical or 3-12-membered heterocycloalkyl radical which is optionally mono- or polysubstituted identically or differently by M and M is C₁-C₆-alkyl or a —COR^(b), CO₂R^(b), —O—R^(b) or NR^(c)R^(d) group, where R^(b), R^(c) and R^(d) are each as specified above, and R¹ and R² are each independently an unbranched or branched C₁-C₅-alkyl group which is optionally substituted by Z or, together with the carbon atom of the chain, form a carbocyclic or heterocyclic ring which is optionally substituted by Z and has a total of 3-7 members, where, when A is hydrogen and R¹ is a methyl radical, R² cannot be a methyl radical or an ethyl radical, A is hydrogen, R¹ and R² cannot together be a ring having 3-4 members, A is a methyl radical, R¹ and R² cannot both be a methyl radical or, together with the carbon atom of the chain, form a cyclopropyl ring, R³ is hydrogen or a C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₃-C₁₀-cycloalkyl, 3-12-membered heterocycloalkyl radical which is optionally mono- or polysubstituted identically or differently by K, or a C₆-C₁₂-aryl or 3-12-membered heteroaryl radical which is optionally mono-, di- or trisubstituted identically or differently by L, and K is cyano, halogen, hydroxyl, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), —C═NOR^(b), —NR^(c)R^(d) or a C₃-C₁₀-cycloalkyl, 3-12-membered hetero-cycloalkyl radical which is optionally mono- or polysubstituted identically or differently by M, or a C₆-C₁₂-aryl or 3-12-membered heteroaryl radical which is optionally mono-, di- or trisubstituted identically or differently by L, with the definition of M specified under A, and L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, a partly or fully fluorinated C₁-C₆-fluoroalkyl, a partly or fully fluorinated C₁-C₆-fluoroalkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkoxy, a mono- or bicyclic (CH₂)_(p)—C₃-C₁₀-cycloalkyl, a mono- or bicyclic 3-12-membered (CH₂)_(p)-heterocycloalkyl radical, (CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, a mono- or bicyclic (CH₂)_(p)—C₆-C₁₂-aryl radical which is optionally substituted by V, a mono- or bicyclic 3-12-membered (CH₂)_(p)-heteroaryl radical which is optionally substituted by V, or —(CH₂)_(p)PO₃(R^(b))₂, —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b), —(CH₂)_(p)NR^(e)CSR^(b), —(CH₂)_(p)NR^(e)S(O)R^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)COOR^(b), —(CH₂)_(p)NR^(e)C(NH)NR^(c)R^(d), —(CH₂)_(p)NR^(e)CSNR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b), —(CH₂)_(p)CSR^(b), —(CH₂)_(p)S(O)R^(b), —(CH₂)_(p)S(O)(NH)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)SO₂OR^(b), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)CSNR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)SR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(b), —(CH₂)_(p)—C═NOR^(b), —O—(CH₂)_(n)—O—, —O—(CH₂)_(n)—CH₂—, —OCH═CH— or —(CH₂)_(n+2)— and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms and n is 1 or 2 and p is 0, 1, 2, 3, 4, 5 or 6, and V is cyano, halogen, nitro, —(CH₂)_(p)OR^(b), —(CH₂)_(p)S(O)₂R^(b), —C(O)R^(b), CO₂R^(b), —O—R^(b), —S—R^(b), SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —OC(O)—NR^(c)R^(d), —C═NOR^(b), —(CH₂)_(p)NR^(c)R^(d), partly or fully fluorinated C₁-C₆-fluoroalkyl or partly or fully fluorinated C₁-C₆-fluoroalkoxy, X is one oxygen atom and two hydrogen atoms Y is (CH₂)_(m), —C≡C— or —CH═CH— where  m=0 or 1, where, when Y is a CH₂ radical, R³ cannot be hydrogen, and R⁴ is a mono- or bicyclic C₆-C₁₂-aryl which is optionally substituted identically or differently by 2 L, or one of the following groups mentioned under B or C: B: 6-membered/6-membered ring systems:

C: 6-membered/5-membered ring systems:

where R⁵ is hydrogen or C₁-C₄-alkyl, or a partly or fully fluorinated C₁-C₄-fluoroalkyl, R^(6a) and R^(6b) are each independently hydrogen, C₁-C₄-alkyl or a partly or fully fluorinated C₁-C₄-fluoroalkyl, or, together with the ring carbon atom, form a 3- to 6-membered ring, and the pharmaceutically acceptable salts thereof.
 2. Compounds according to claim 1, in which A is a hydrogen.
 3. Compounds according to claim 2, in which Y is —C≡C—, R¹ and R² together with the carbon atom of the chain form a carbocyclic or heterocyclic 3-6-membered ring and R³ is optionally K-substituted C₁-C₈-alkyl, a C₆-C₁₂-aryl optionally mono-, di- or trisubstituted identically or differently by L, or 3- to 12-membered heteroaryl.
 4. Compounds according to claim 2, in which Y is (CH₂)_(m) and R³ is a C₆-C₁₂-aryl optionally mono-, di- or trisubstituted identically or differently by L or 3- to 12-membered heteroaryl, and R⁴ is mono- or bicyclic aryl disubstituted identically or differently by L, or one of the B groups specified under R⁴ with linkage at position 6 or C with linkage at position
 5. 5. Compounds according to claim 4, in which m=1.
 6. Compounds according to claim 5, in which R⁴ is a phenyl ring disubstituted identically or differently by L.
 7. Compounds according to claim 6, in which the phenyl ring is substituted by a cyano radical, by chlorine and/or by a trifluoromethyl radical.
 8. Compounds according to claim 4, in which R⁴ has the following definition:


9. Compounds according to claim 8, in which R⁵ is methyl or ethyl R⁶ is hydrogen.
 10. Compounds according to claim 2, in which p is 0, 1 or 2, and L is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, partly or fully fluorinated C₁-C₆-fluoroalkyl, —(CH₂)_(p)CN, (CH₂)_(p)Hal, (CH₂)_(p)NO₂, (CH₂)_(p)—C₆-C₁₂-aryl, —(CH₂)_(p)-heteroaryl, —(CH₂)_(p)NR^(c)R^(d), —(CH₂)_(p)NR^(e)COR^(b), —(CH₂)_(p)NR^(e)S(O)₂R^(b), —(CH₂)_(p)NR^(e)CONR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)NR^(c)R^(d), —(CH₂)_(p)NR^(e)S(O)₂NR^(c)R^(d), —(CH₂)_(p)COR^(b), —(CH₂)_(p)S(O)R^(b), —(CH₂)_(p)S(O)₂R^(b), —(CH₂)_(p)S(O)₂NR^(c)R^(d), —(CH₂)_(p)CO₂R^(b), —(CH₂)_(p)CONR^(c)R^(d), —(CH₂)_(p)OR^(b), —(CH₂)_(p)CR^(b)(OH)—R^(b) and Z is cyano, halogen, hydroxyl, nitro, —C(O)R^(b), CO₂R^(b), —O—R^(b), —SO₂NR^(c)R^(d), —C(O)—NR^(c)R^(d), —NR^(c)R^(d), —NR^(e)COR^(b), —NR^(e)S(O)R^(b), —NR^(e)S(O)₂R^(b), —NR^(e)CONR^(c)R^(d), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b), —CR^(b)(OH)—R^(b) or a C₃-C₁₀-cycloalkyl or heterocycloalkyl optionally mono- or polysubstituted identically or differently by M.
 11. Compounds according to claim 2, in which R¹ and R² together with the carbon atom of the chain form a cyclopropyl, cyclopentyl or cyclohexyl ring.
 12. Compounds according to claim 2, in which R¹ and R² together with the carbon atom of the chain form a tetrahydropyranyl, piperidinyl or tetrahydrothiopyranyl ring.
 13. Compounds according to one of the preceding claims, specifically

    No. Racemic or enantiomer     R3   1   2   3 rac + −

  4   5   6 rac + −

  7   8   9 rac + −

 10  11  12 rac + −

 13  14  15 rac + −

 16  17  18 rac + −

 19  20  21 rac + −

 22  23  24 rac + −

 25  26  27 rac + −

 28  29  30 rac + −

 31  32  33 rac + −

 34  35  36 rac + −

 37  38  39 rac + −

 40  41  42 rac + −

 43  44  45 rac + −

 46  47  48 rac + −

 49  50  51 rac + −

 52  53  54 rac + −

 55  56  57 rac + −

 58  59  60 rac + −

 61  62  63 rac + −

 64  65  66 rac + −

 67  68  69 rac + −

 70  71  72 rac + −

 73  74  75 rac + −

 76  77  78 rac + −

 79  80  81 rac + −

 82  83  84 rac + −

 85  86  87 rac + −

 88  89  90 rac + −

 91  92  93 rac + −

 94  95  96 rac + −

 97  98  99 rac + −

 100  101  102 rac + −

 103  104  105 rac + −

 106  107  108 rac + −

 109  110  111 rac + −

 112  113  114 rac + −

 115  116  117 rac + −

 118  119  120 rac + −

 121  122  123 rac + −

 124  125  126 rac + −

 127  128  129 rac + −

 130  131  132 rac + −

 133  134  135 rac + −

 136  137  138 rac + −

 139  140  141 rac + −

 142  143  144 rac + −

 145  146  147 rac + −

 148  149  150 rac + −

 151  152  153 rac + −

 154  155  156 rac + −

 157  158  159 rac + −

 160  161  162 rac + −

 163  164  165 rac + −

 166  167  168 rac + −

 169  170  171 rac + −

 172  173  174 rac + −

 175  176  177 rac + −

 178  179  180 rac + −

 181  182  183 rac + −

 184  185  186 rac + −

 187  188  189 rac + −

 190  191  192 rac + −

 193  194  195 rac + −

 196  197  198 rac + −

 199  200  201 rac + −

 202  203  204 rac + −

 205  206  207 rac + −

 208  209  210 rac + −

 211  212  213 rac + −

 214  215  216 rac + −

 217  218  219 rac + −

 220  221  222 rac + −

 223  224  225 rac + −

 226  227  228 rac + −

 229  230  231 rac + −

 232  233  234 rac + −

 235  236  237 rac + −

 238  239  240 rac + −

 241  242  243 rac + −

 244  245  246 rac + −

 247  248  249 rac + −

 250  251  252 rac + −

 253  254  255 rac + −

 256  257  258 rac + −

 259  260  261 rac + −

    No. Racemic or enantiomer     R3  262  263  264 rac + −

 265  266  267 rac + −

 268  269  270 rac + −

 271  272  273 rac + −

 274  275  276 rac + −

 277  278  279 rac + −

 280  281  282 rac + −

 283  284  285 rac + −

 286  287  288 rac + −

 289  290  291 rac + −

 292  293  294 rac + −

 295  296  297 rac + −

 298  299  300 rac + −

 301  302  303 rac + −

 304  305  306 rac + −

 307  308  309 rac + −

 310  311  312 rac + −

 313  314  315 rac + −

 316  317  318 rac + −

 319  320  321 rac + −

 322  323  324 rac + −

 325  326  327 rac + −

 328  329  330 rac + −

 331  332  333 rac + −

 334  335  336 rac + −

 337  338  339 rac + −

 340  341  342 rac + −

 343  344  345 rac + −

 346  347  348 rac + −

 349  350  351 rac + −

 352  353  354 rac + −

 355  356  357 rac + −

 358  359  360 rac + −

 361  362  363 rac + −

 364  365  366 rac + −

 367  368  369 rac + −

 370  371  372 rac + −

 373  374  375 rac + −

 376  377  378 rac + −

 379  380  381 rac + −

 382  383  384 rac + −

 385  386  387 rac + −

 388  389  390 rac + −

 391  392  393 rac + −

 394  395  396 rac + −

 397  398  399 rac + −

 400  401  402 rac + −

 403  404  405 rac + −

 406  407  408 rac + −

 409  410  411 rac + −

 412  413  414 rac + −

 415  416  417 rac + −

 418  419  420 rac + −

 421  422  423 rac + −

 424  425  426 rac + −

 427  428  429 rac + −

 430  431  432 rac + −

 433  434  435 rac + −

 436  437  438 rac + −

 439  440  441 rac + −

 442  443  444 rac + −

 445  446  447 rac + −

 448  449  450 rac + −

 451  452  453 rac + −

 454  455  456 rac + −

 457  458  459 rac + −

 460  461  462 rac + −

 463  464  465 rac + −

 466  467  468 rac + −

 469  470  471 rac + −

 472  473  474 rac + −

 475  476  477 rac + −

 478  479  480 rac + −

 481  482  483 rac + −

 484  485  486 rac + −

 487  488  489 rac + −

 490  491  492 rac + −

 493  494  495 rac + −

 496  497  498 rac + −

 499  500  501 rac + −

 502  503  504 rac + −

 505  506  507 rac + −

 508  509  510 rac + −

 511  512  513 rac + −

 514  515  516 rac + −

 517  518  519 rac + −

 520  521  522 rac + −

    No. Racemic or enantiomer     R3  523  524  525 rac + −

 526  527  528 rac + −

 529  530  531 rac + −

 532  533  534 rac + −

 535  536  537 rac + −

 538  539  540 rac + −

 541  542  543 rac + −

 544  545  546 rac + −

 547  548  549 rac + −

 550  551  552 rac + −

 553  554  555 rac + −

 556  557  558 rac + −

 559  560  561 rac + −

 562  563  564 rac + −

 565  566  567 rac + −

 568  569  570 rac + −

 571  572  573 rac + −

 574  575  576 rac + −

 577  578  579 rac + −

 580  581  582 rac + −

 583  584  585 rac + −

 586  587  588 rac + −

 589  590  591 rac + −

 592  593  594 rac + −

 595  596  597 rac + −

 598  599  600 rac + −

 601  602  603 rac + −

 604  605  606 rac + −

 607  608  609 rac + −

 610  611  612 rac + −

 613  614  615 rac + −

 616  617  618 rac + −

 619  620  621 rac + −

 622  623  624 rac + −

 625  626  627 rac + −

 628  629  630 rac + −

 631  632  633 rac + −

 634  635  636 rac + −

 637  638  639 rac + −

 640  641  642 rac + −

 643  644  645 rac + −

 646  647  648 rac + −

 649  650  651 rac + −

 652  653  654 rac + −

 655  656  657 rac + −

 658  659  660 rac + −

 661  662  663 rac + −

 664  665  666 rac + −

 667  668  669 rac + −

 670  671  672 rac + −

 673  674  675 rac + −

 676  677  678 rac + −

 679  680  681 rac + −

 682  683  684 rac + −

 685  686  687 rac + −

 688  689  690 rac + −

 691  692  693 rac + −

 694  695  696 rac + −

 697  698  699 rac + −

 700  701  702 rac + −

 703  704  705 rac + −

 706  707  708 rac + −

 709  710  711 rac + −

 712  713  714 rac + −

 715  716  717 rac + −

 718  719  720 rac + −

 721  722  723 rac + −

 724  725  726 rac + −

 727  728  729 rac + −

 730  731  732 rac + −

 733  734  735 rac + −

 736  737  738 rac + −

 739  740  741 rac + −

 742  743  744 rac + −

 745  746  747 rac + −

 748  749  750 rac + −

 751  752  753 rac + −

 754  755  756 rac + −

 757  758  759 rac + −

 760  761  762 rac + −

 763  764  765 rac + −

 766  767  768 rac + −

 769  770  771 rac + −

 772  773  774 rac + −

 775  776  777 rac + −

 778  779  780 rac + −

 781  782  783 rac + −

    No. Racemic or enantiomer     R3  784  785  786 rac + −

 787  788  789 rac + −

 790  791  792 rac + −

 793  794  795 rac + −

 796  797  798 rac + −

 799  800  801 rac + −

 802  803  804 rac + −

 805  806  807 rac + −

 808  809  810 rac + −

 811  812  813 rac + −

 814  815  816 rac + −

 817  818  819 rac + −

 820  821  822 rac + −

 823  824  825 rac + −

 826  827  828 rac + −

 829  830  831 rac + −

 832  833  834 rac + −

 835  836  837 rac + −

 838  839  840 rac + −

 841  842  843 rac + −

 844  845  846 rac + −

 847  848  849 rac + −

 850  851  852 rac + −

 853  854  855 rac + −

 856  857  858 rac + −

 859  860  861 rac + −

 862  863  864 rac + −

 865  866  867 rac + −

 868  869  870 rac + −

 871  872  873 rac + −

 874  875  876 rac + −

 877  878  879 rac + −

 880  881  882 rac + −

 883  884  885 rac + −

 886  887  888 rac + −

 889  890  891 rac + −

 892  893  894 rac + −

 895  896  897 rac + −

 898  899  900 rac + −

 901  902  903 rac + −

 904  905  906 rac + −

 907  908  909 rac + −

 910  911  912 rac + −

 913  914  915 rac + −

 916  917  918 rac + −

 919  920  921 rac + −

 922  923  924 rac + −

 925  926  927 rac + −

 928  929  930 rac + −

 931  932  933 rac + −

 934  935  936 rac + −

 937  938  939 rac + −

 940  941  942 rac + −

 943  944  945 rac + −

 946  947  948 rac + −

 949  950  951 rac + −

 952  953  954 rac + −

 955  956  957 rac + −

 958  959  960 rac + −

 961  962  963 rac + −

 964  965  966 rac + −

 967  968  969 rac + −

 970  971  972 rac + −

 973  974  975 rac + −

 976  977  978 rac + −

 979  980  981 rac + −

 982  983  984 rac + −

 985  986  987 rac + −

 988  989  990 rac + −

 991  992  993 rac + −

 994  995  996 rac + −

 997  998  999 rac + −

1000 1001 1002 rac + −

1003 1004 1005 rac + −

1006 1007 1008 rac + −

1009 1010 1011 rac + −

1012 1013 1014 rac + −

1015 1016 1017 rac + −

1018 1019 1020 rac + −

1021 1022 1023 rac + −

1024 1025 1026 rac + −

1027 1028 1029 rac + −

1030 1031 1032 rac + −

1033 1034 1035 rac + −

1036 1037 1038 rac + −

1039 1040 1041 rac + −

1042 1043 1044 rac + −

    No. Racemic or enantiomer     R3 1045 1046 1047 rac + −

1048 1049 1050 rac + −

1051 1052 1053 rac + −

1054 1055 1056 rac + −

1057 1058 1059 rac + −

1060 1061 1062 rac + −

1063 1064 1065 rac + −

1066 1067 1068 rac + −

1069 1070 1071 rac + −

1072 1073 1074 rac + −

1075 1076 1077 rac + −

1078 1079 1080 rac + −

1081 1082 1083 rac + −

1084 1085 1086 rac + −

1087 1088 1089 rac + −

1090 1091 1092 rac + −

1093 1094 1095 rac + −

1096 1097 1098 rac + −

1099 1100 1101 rac + −

1102 1103 1104 rac + −

1105 1106 1107 rac + −

1108 1109 1110 rac + −

1111 1112 1113 rac + −

1114 1115 1116 rac + −

1117 1118 1119 rac + −

1120 1121 1122 rac + −

1123 1124 1125 rac + −

1126 1127 1128 rac + −

1129 1130 1131 rac + −

1132 1133 1134 rac + −

1135 1136 1137 rac + −

1138 1139 1140 rac + −

1141 1142 1143 rac + −

1144 1145 1146 rac + −

1147 1148 1149 rac + −

1150 1151 1152 rac + −

1153 1154 1155 rac + −

1156 1157 1158 rac + −

1159 1160 1161 rac + −

1162 1163 1164 rac + −

1165 1166 1167 rac + −

1168 1169 1170 rac + −

1171 1172 1173 rac + −

1174 1175 1176 rac + −

1177 1178 1179 rac + −

1180 1181 1182 rac + −

1183 1184 1185 rac + −

1186 1187 1188 rac + −

1189 1190 1191 rac + −

1192 1193 1194 rac + −

1195 1196 1197 rac + −

1198 1199 1200 rac + −

1201 1202 1203 rac + −

1204 1205 1206 rac + −

1207 1208 1209 rac + −

1210 1211 1212 rac + −

1213 1214 1215 rac + −

1216 1217 1218 rac + −

1219 1220 1221 rac + −

1222 1223 1224 rac + −

1225 1226 1227 rac + −

1228 1229 1230 rac + −

1231 1232 1233 rac + −

1234 1235 1236 rac + −

1237 1238 1239 rac + −

1240 1241 1242 rac + −

1243 1244 1245 rac + −

1246 1247 1248 rac + −

1249 1250 1251 rac + −

1252 1253 1254 rac + −

1255 1256 1257 rac + −

1258 1259 1260 rac + −

1261 1262 1263 rac + −

1264 1265 1266 rac + −

1267 1268 1269 rac + −

1270 1271 1272 rac + −

1273 1274 1275 rac + −

1276 1277 1278 rac + −

1279 1280 1281 rac + −

1282 1283 1284 rac + −

1285 1286 1287 rac + −

1288 1289 1290 rac + −

1291 1292 1293 rac + −

1294 1295 1296 rac + −

1297 1298 1299 rac + −

1300 1301 1302 rac + −

1303 1304 1305 rac + −

    No. Racemic or enantiomer     R3 1306 1307 1308 rac + −

1309 1310 1311 rac + −

1312 1313 1314 rac + −

1315 1316 1317 rac + −

1318 1319 1320 rac + −

1321 1322 1323 rac + −

1324 1325 1326 rac + −

1327 1328 1329 rac + −

1330 1331 1332 rac + −

1333 1334 1335 rac + −

1336 1337 1338 rac + −

1339 1340 1341 rac + −

1342 1343 1344 rac + −

1345 1346 1347 rac + −

1348 1349 1350 rac + −

1351 1352 1353 rac + −

1354 1355 1356 rac + −

1357 1358 1359 rac + −

1360 1361 1362 rac + −

1363 1364 1365 rac + −

1366 1367 1368 rac + −

1369 1370 1371 rac + −

1372 1373 1374 rac + −

1375 1376 1377 rac + −

1378 1379 1380 rac + −

1381 1382 1383 rac + −

1384 1385 1386 rac + −

1387 1388 1389 rac + −

1390 1391 1392 rac + −

1393 1394 1395 rac + −

1396 1397 1398 rac + −

1399 1400 1401 rac + −

1402 1403 1404 rac + −

1405 1406 1407 rac + −

1408 1409 1410 rac + −

1411 1412 1413 rac + −

1414 1415 1416 rac + −

1417 1418 1419 rac + −

1420 1421 1422 rac + −

1423 1424 1425 rac + −

1426 1427 1428 rac + −

1429 1430 1431 rac + −

1432 1433 1434 rac + −

1435 1436 1437 rac + −

1438 1439 1440 rac + −

1441 1442 1443 rac + −

1444 1445 1446 rac + −

1447 1448 1449 rac + −

1450 1451 1452 rac + −

1453 1454 1455 rac + −

1456 1457 1458 rac + −

1459 1460 1461 rac + −

1462 1463 1464 rac + −

1465 1466 1467 rac + −

1468 1469 1470 rac + −

1471 1472 1473 rac + −

1474 1475 1476 rac + −

1477 1478 1479 rac + −

1480 1481 1482 rac + −

1483 1484 1485 rac + −

1486 1487 1488 rac + −

1489 1490 1491 rac + −

1492 1493 1494 rac + −

1495 1496 1497 rac + −

1498 1499 1500 rac + −

1501 1502 1503 rac + −

1504 1505 1506 rac + −

1507 1508 1509 rac + −

1510 1511 1512 rac + −

1513 1514 1515 rac + −

1516 1517 1518 rac + −

1519 1520 1521 rac + −

1522 1523 1524 rac + −

1525 1526 1527 rac + −

1528 1529 1530 rac + −

1531 1532 1533 rac + −

1534 1535 1536 rac + −

1537 1538 1539 rac + −

1540 1541 1542 rac + −

1543 1544 1545 rac + −

1546 1547 1548 rac + −

1549 1550 1551 rac + −

1552 1553 1554 rac + −

1555 1556 1557 rac + −

1558 1559 1560 rac + −

1561 1562 1563 rac + −

1564 1565 1566 rac + −

    No. Racemic or enantiomer     R3 1567 1568 1569 rac + −

1570 1571 1572 rac + −

1573 1574 1575 rac + −

1576 1577 1578 rac + −

1579 1580 1581 rac + −

1582 1583 1584 rac + −

1585 1586 1587 rac + −

1588 1589 1590 rac + −

1591 1592 1593 rac + −

1594 1595 1596 rac + −

1597 1598 1599 rac + −

1600 1601 1602 rac + −

1603 1604 1605 rac + −

1606 1607 1608 rac + −

1609 1610 1611 rac + −

1612 1613 1614 rac + −

1615 1616 1617 rac + −

1618 1619 1620 rac + −

1621 1622 1623 rac + −

1624 1625 1626 rac + −

1627 1628 1629 rac + −

1630 1631 1632 rac + −

1633 1634 1635 rac + −

1636 1637 1638 rac + −

1639 1640 1641 rac + −

1642 1643 1644 rac + −

1645 1646 1647 rac + −

1648 1649 1650 rac + −

1651 1652 1653 rac + −

1654 1655 1656 rac + −

1657 1658 1659 rac + −

1660 1661 1662 rac + −

1663 1664 1665 rac + −

1666 1667 1668 rac + −

1669 1670 1671 rac + −

1672 1673 1674 rac + −

1675 1676 1677 rac + −

1678 1679 1680 rac + −

1681 1682 1683 rac + −

1684 1685 1686 rac + −

1687 1688 1689 rac + −

1690 1691 1692 rac + −

1693 1694 1695 rac + −

1696 1697 1698 rac + −

1699 1700 1701 rac + −

1702 1703 1704 rac + −

1705 1706 1707 rac + −

1708 1709 1710 rac + −

1711 1712 1713 rac + −

1714 1715 1716 rac + −

1717 1718 1719 rac + −

1720 1721 1722 rac + −

1723 1724 1725 rac + −

1726 1727 1728 rac + −

1729 1730 1731 rac + −

1732 1733 1734 rac + −

1735 1736 1737 rac + −

1738 1739 1740 rac + −

1741 1742 1743 rac + −

1744 1745 1746 rac + −

1747 1748 1749 rac + −

1750 1751 1752 rac + −

1753 1754 1755 rac + −

1756 1757 1758 rac + −

1759 1760 1761 rac + −

1762 1763 1764 rac + −

1765 1766 1767 rac + −

1768 1769 1770 rac + −

1771 1772 1773 rac + −

1774 1775 1776 rac + −

1777 1778 1779 rac + −

1780 1781 1782 rac + −

1783 1784 1785 rac + −

1786 1787 1788 rac + −

1789 1790 1791 rac + −

1792 1793 1794 rac + −

1795 1796 1797 rac + −

1798 1799 1800 rac + −

1801 1802 1803 rac + −

1804 1805 1806 rac + −

1807 1808 1809 rac + −

1810 1811 1812 rac + −

1813 1814 1815 rac + −

1816 1817 1818 rac + −

1819 1820 1821 rac + −

1822 1823 1824 rac + −

1825 1826 1827 rac + −

    No. Racemic or enantiomer     R3 1828 1829 1830 rac + −

1831 1832 1833 rac + −

1834 1835 1836 rac + −

1837 1838 1839 rac + −

1840 1841 1842 rac + −

1843 1844 1845 rac + −

1846 1847 1848 rac + −

1849 1850 1851 rac + −

1852 1853 1854 rac + −

1855 1856 1857 rac + −

1858 1859 1860 rac + −

1861 1862 1863 rac + −

1864 1865 1866 rac + −

1867 1868 1869 rac + −

1870 1871 1872 rac + −

1873 1874 1875 rac + −

1876 1877 1878 rac + −

1879 1880 1881 rac + −

1882 1883 1884 rac + −

1885 1886 1887 rac + −

1888 1889 1890 rac + −

1891 1892 1893 rac + −

1894 1895 1896 rac + −

1897 1898 1899 rac + −

1900 1901 1902 rac + −

1903 1904 1905 rac + −

1906 1907 1908 rac + −

1909 1910 1911 rac + −

1912 1913 1914 rac + −

1915 1916 1917 rac + −

1918 1919 1920 rac + −

1921 1922 1923 rac + −

1924 1925 1926 rac + −

1927 1928 1929 rac + −

1930 1931 1932 rac + −

1933 1934 1935 rac + −

1936 1937 1938 rac + −

1939 1940 1941 rac + −

1942 1943 1944 rac + −

1945 1946 1947 rac + −

1948 1949 1950 rac + −

1951 1952 1953 rac + −

1954 1955 1956 rac + −

1957 1958 1959 rac + −

1960 1961 1962 rac + −

1963 1964 1965 rac + −

1966 1967 1968 rac + −

1969 1970 1971 rac + −

1972 1973 1974 rac + −

1975 1976 1977 rac + −

1978 1979 1980 rac + −

1981 1982 1983 rac + −

1984 1985 1986 rac + −

1987 1988 1989 rac + −

1990 1991 1992 rac + −

1993 1994 1995 rac + −

1996 1997 1998 rac + −

1999 2000 2001 rac + −

2002 2003 2004 rac + −

2005 2006 2007 rac + −

2008 2009 2010 rac + −

2011 2012 2013 rac + −

2014 2015 2016 rac + −

2017 2018 2019 rac + −

2020 2021 2022 rac + −

2023 2024 2025 rac + −

2026 2027 2028 rac + −

2029 2030 2031 rac + −

2032 2033 2034 rac + −

2035 2036 2037 rac + −

2038 2039 2040 rac + −

2041 2042 2043 rac + −

2044 2045 2046 rac + −

2047 2048 2049 rac + −

2050 2051 2052 rac + −

2053 2054 2055 rac + −

2056 2057 2058 rac + −

2059 2060 2061 rac + −

2062 2063 2064 rac + −

2065 2066 2067 rac + −

2068 2069 2070 rac + −

2071 2072 2073 rac + −

2074 2075 2076 rac + −

2077 2078 2079 rac + −

2080 2081 2082 rac + −

2083 2084 2085 rac + −

2086 2087 2088 rac + −

    No. Racemic or enantiomer     R3 2089 2090 2091 rac + −

2092 2093 2094 rac + −

2095 2096 2097 rac + −

2098 2099 2100 rac + −

2101 2102 2103 rac + −

2104 2105 2106 rac + −

2107 2108 2109 rac + −

2110 2111 2112 rac + −

2113 2114 2115 rac + −

2116 2117 2118 rac + −

2119 2120 2121 rac + −

2122 2123 2124 rac + −

2125 2126 2127 rac + −

2128 2129 2130 rac + −

2131 2132 2133 rac + −

2134 2135 2136 rac + −

2137 2138 2139 rac + −

2140 2141 2142 rac + −

2143 2144 2145 rac + −

2146 2147 2148 rac + −

2149 2150 2151 rac + −

2152 2153 2154 rac + −

2155 2156 2157 rac + −

2158 2159 2160 rac + −

2161 2162 2163 rac + −

2164 2165 2166 rac + −

2167 2168 2169 rac + −

2170 2171 2172 rac + −

2173 2174 2175 rac + −

2176 2177 2178 rac + −

2179 2180 2181 rac + −

2182 2183 2184 rac + −

2185 2186 2187 rac + −

2188 2189 2190 rac + −

2191 2192 2193 rac + −

2194 2195 2196 rac + −

2197 2198 2199 rac + −

2200 2201 2202 rac + −

2203 2204 2205 rac + −

2206 2207 2208 rac + −

2209 2210 2211 rac + −

2212 2213 2214 rac + −

2215 2216 2217 rac + −

2218 2219 2220 rac + −

2221 2222 2223 rac + −

2224 2225 2226 rac + −

2227 2228 2229 rac + −

2230 2231 2232 rac + −

2233 2234 2235 rac + −

2236 2237 2238 rac + −

2239 2240 2241 rac + −

2242 2243 2244 rac + −

2245 2246 2247 rac + −

2248 2249 2250 rac + −

2251 2252 2253 rac + −

2254 2255 2256 rac + −

2257 2258 2259 rac + −

2260 2261 2262 rac + −

2263 2264 2265 rac + −

2266 2267 2268 rac + −

2269 2270 2271 rac + −

2272 2273 2274 rac + −

2275 2276 2277 rac + −

2278 2279 2280 rac + −

2281 2282 2283 rac + −

2284 2285 2286 rac + −

2287 2288 2289 rac + −

2290 2291 2292 rac + −

2293 2294 2295 rac + −

2296 2297 2298 rac + −

2299 2300 2301 rac + −

2302 2303 2304 rac + −

2305 2306 2307 rac + −

2308 2309 2310 rac + −

2311 2312 2313 rac + −

2314 2315 2316 rac + −

2317 2318 2319 rac + −

2320 2321 2322 rac + −

2323 2324 2325 rac + −

2326 2327 2328 rac + −

2329 2330 2331 rac + −

2332 2333 2334 rac + −

2335 2336 2337 rac + −

2338 2339 2340 rac + −

2341 2342 2343 rac + −

2344 2345 2346 rac + −

2347 2348 2349 rac + −

    No. Racemic or enantiomer     R3 2350 2351 2352 rac + −

2353 2354 2355 rac + −

2356 2357 2358 rac + −

2359 2360 2361 rac + −

2362 2363 2364 rac + −

2365 2366 2367 rac + −

2368 2369 2370 rac + −

2371 2372 2373 rac + −

2374 2375 2376 rac + −

2377 2378 2379 rac + −

2380 2381 2382 rac + −

2383 2384 2385 rac + −

2386 2387 2388 rac + −

2389 2390 2391 rac + −

2392 2393 2394 rac + −

2395 2396 2397 rac + −

2398 2399 2400 rac + −

2401 2402 2403 rac + −

2404 2405 2406 rac + −

2407 2408 2409 rac + −

2410 2411 2412 rac + −

2413 2414 2415 rac + −

2416 2417 2418 rac + −

2419 2420 2421 rac + −

2422 2423 2424 rac + −

2425 2426 2427 rac + −

2428 2429 2430 rac + −

2431 2432 2433 rac + −

2434 2435 2436 rac + −

2437 2438 2439 rac + −

2440 2441 2442 rac + −

2443 2444 2445 rac + −

2446 2447 2448 rac + −

2449 2450 2451 rac + −

2452 2453 2454 rac + −

2455 2456 2457 rac + −

2458 2459 2460 rac + −

2461 2462 2463 rac + −

2464 2465 2466 rac + −

2467 2468 2469 rac + −

2470 2471 2472 rac + −

2473 2474 2475 rac + −

2476 2477 2478 rac + −

2479 2480 2481 rac + −

2482 2483 2484 rac + −

2485 2486 2487 rac + −

2488 2489 2490 rac + −

2491 2492 2493 rac + −

2494 2495 2496 rac + −

2497 2498 2499 rac + −

2500 2501 2502 rac + −

2503 2504 2505 rac + −

2506 2507 2508 rac + −

2509 2510 2511 rac + −

2512 2513 2514 rac + −

2515 2516 2517 rac + −

2518 2519 2520 rac + −

2521 2522 2523 rac + −

2524 2525 2526 rac + −

2527 2528 2529 rac + −

2530 2531 2532 rac + −

2533 2534 2535 rac + −

2536 2537 2538 rac + −

2539 2540 2541 rac + −

2542 2543 2544 rac + −

2545 2546 2547 rac + −

2548 2549 2550 rac + −

2551 2552 2553 rac + −

2554 2555 2556 rac + −

2557 2558 2559 rac + −

2560 2561 2562 rac + −

2563 2564 2565 rac + −

2566 2567 2568 rac + −

2569 2570 2571 rac + −

2572 2573 2574 rac + −

2575 2576 2577 rac + −

2578 2579 2580 rac + −

2581 2582 2583 rac + −

2584 2585 2586 rac + −

2587 2588 2589 rac + −

2590 2591 2592 rac + −

2593 2594 2595 rac + −

2596 2597 2598 rac + −

2599 2600 2601 rac + −

2602 2603 2604 rac + −

2605 2606 2607 rac + −

2608 2609 2610 rac + −

    No. Racemic or enantiomer     R3 2611 2612 2613 rac + −

2614 2615 2616 rac + −

2617 2618 2619 rac + −

2620 2621 2622 rac + −

2623 2624 2625 rac + −

2626 2627 2628 rac + −

2629 2630 2631 rac + −

2632 2633 2634 rac + −

2635 2636 2637 rac + −

2638 2639 2640 rac + −

2641 2642 2643 rac + −

2644 2645 2646 rac + −

2647 2648 2649 rac + −

2650 2651 2652 rac + −

2653 2654 2655 rac + −

2656 2657 2658 rac + −

2659 2660 2661 rac + −

2662 2663 2664 rac + −

2665 2666 2667 rac + −

2668 2669 2670 rac + −

2671 2672 2673 rac + −

2674 2675 2676 rac + −

2677 2678 2679 rac + −

2680 2681 2682 rac + −

2683 2684 2685 rac + −

2686 2687 2688 rac + −

2689 2690 2691 rac + −

2692 2693 2694 rac + −

2695 2696 2697 rac + −

2698 2699 2700 rac + −

2701 2702 2703 rac + −

2704 2705 2706 rac + −

2707 2708 2709 rac + −

2710 2711 2712 rac + −

2713 2714 2715 rac + −

2716 2717 2718 rac + −

2719 2720 2721 rac + −

2722 2723 2724 rac + −

2725 2726 2727 rac + −

2728 2729 2730 rac + −

2731 2732 2733 rac + −

2734 2735 2736 rac + −

2737 2738 2739 rac + −

2740 2741 2742 rac + −

2743 2744 2745 rac + −

2746 2747 2748 rac + −

2749 2750 2751 rac + −

2752 2753 2754 rac + −

2755 2756 2757 rac + −

2758 2759 2760 rac + −

2761 2762 2763 rac + −

2764 2765 2766 rac + −

2767 2768 2769 rac + −

2770 2771 2772 rac + −

2773 2774 2775 rac + −

2776 2777 2778 rac + −

2779 2780 2781 rac + −

2782 2783 2784 rac + −

2785 2786 2787 rac + −

2788 2789 2790 rac + −

2791 2792 2793 rac + −

2794 2795 2796 rac + −

2797 2798 2799 rac + −

2800 2801 2802 rac + −

2803 2804 2805 rac + −

2806 2807 2808 rac + −

2809 2810 2811 rac + −

2812 2813 2814 rac + −

2815 2816 2817 rac + −

2818 2819 2820 rac + −

2821 2822 2823 rac + −

2824 2825 2826 rac + −

2827 2828 2829 rac + −

2830 2831 2832 rac + −

2833 2834 2835 rac + −

2836 2837 2838 rac + −

2839 2840 2841 rac + −

2842 2843 2844 rac + −

2845 2846 2847 rac + −

2848 2849 2850 rac + −

2851 2852 2853 rac + −

2854 2855 2856 rac + −

2857 2858 2859 rac + −

2860 2861 2862 rac + −

2863 2864 2865 rac + −

2866 2867 2868 rac + −

2869 2870 2871 rac + −

    No. Racemic or enantiomer     R3 2872 2873 2874 rac + −

2875 2876 2877 rac + −

2878 2879 2880 rac + −

2881 2882 2883 rac + −

2884 2885 2886 rac + −

2887 2888 2889 rac + −

2890 2891 2892 rac + −

2893 2894 2895 rac + −

2896 2897 2898 rac + −

2899 2900 2901 rac + −

2902 2903 2904 rac + −

2905 2906 2907 rac + −

2908 2909 2910 rac + −

2911 2912 2913 rac + −

2914 2915 2916 rac + −

2917 2918 2919 rac + −

2920 2921 2922 rac + −

2923 2924 2925 rac + −

2926 2927 2928 rac + −

2929 2930 2931 rac + −

2932 2933 2934 rac + −

2935 2936 2937 rac + −

2938 2939 2940 rac + −

2941 2942 2943 rac + −

2944 2945 2946 rac + −

2947 2948 2949 rac + −

2950 2951 2952 rac + −

2953 2954 2955 rac + −

2956 2957 2958 rac + −

2959 2960 2961 rac + −

2962 2963 2964 rac + −

2965 2966 2967 rac + −

2968 2969 2970 rac + −

2971 2972 2973 rac + −

2974 2975 2976 rac + −

2977 2978 2979 rac + −

2980 2981 2982 rac + −

2983 2984 2985 rac + −

2986 2987 2988 rac + −

2989 2990 2991 rac + −

2992 2993 2994 rac + −

2995 2996 2997 rac + −

2998 2999 3000 rac + −

3001 3002 3003 rac + −

3004 3005 3006 rac + −

3007 3008 3009 rac + −

3010 3011 3012 rac + −

3013 3014 3015 rac + −

3016 3017 3018 rac + −

3019 3020 3021 rac + −

3022 3023 3024 rac + −

3025 3026 3027 rac + −

3028 3029 3030 rac + −

3031 3032 3033 rac + −

3034 3035 3036 rac + −

3037 3038 3039 rac + −

3040 3041 3042 rac + −

3043 3044 3045 rac + −

3046 3047 3048 rac + −

3049 3050 3051 rac + −

3052 3053 3054 rac + −

3055 3056 3057 rac + −

3058 3059 3060 rac + −

3061 3062 3063 rac + −

3064 3065 3066 rac + −

3067 3068 3069 rac + −

3070 3071 3072 rac + −

3073 3074 3075 rac + −

3076 3077 3078 rac + −

3079 3080 3081 rac + −

3082 3083 3084 rac + −

3085 3086 3087 rac + −

3088 3089 3090 rac + −

3091 3092 3093 rac + −

3094 3095 3096 rac + −

3097 3098 3099 rac + −

3100 3101 3102 rac + −

3103 3104 3105 rac + −

3106 3107 3108 rac + −

3109 3110 3111 rac + −

3112 3113 3114 rac + −

3115 3116 3117 rac + −

3118 3119 3120 rac + −

3121 3122 3123 rac + −

3124 3125 3126 rac + −

3127 3128 3129 rac + −

3130 3131 3132 rac + −

    No. Racemic or enantiomer     R3 3133 3134 3135 rac + −

3136 3137 3138 rac + −

3139 3140 3141 rac + −

3142 3143 3144 rac + −

3145 3146 3147 rac + −

3148 3149 3150 rac + −

3151 3152 3153 rac + −

3154 3155 3156 rac + −

3157 3158 3159 rac + −

3160 3161 3162 rac + −

3163 3164 3165 rac + −

3166 3167 3168 rac + −

3169 3170 3171 rac + −

3172 3173 3174 rac + −

3175 3176 3177 rac + −

3178 3179 3180 rac + −

3181 3182 3183 rac + −

3184 3185 3186 rac + −

3187 3188 3189 rac + −

3190 3191 3192 rac + −

3193 3194 3195 rac + −

3196 3197 3198 rac + −

3199 3200 3201 rac + −

3202 3203 3204 rac + −

3205 3206 3207 rac + −

3208 3209 3210 rac + −

3211 3212 3213 rac + −

3214 3215 3216 rac + −

3217 3218 3219 rac + −

3220 3221 3222 rac + −

3223 3224 3225 rac + −

3226 3227 3228 rac + −

3229 3230 3231 rac + −

3232 3233 3234 rac + −

3235 3236 3237 rac + −

3238 3239 3240 rac + −

3241 3242 3243 rac + −

3244 3245 3246 rac + −

3247 3248 3249 rac + −

3250 3251 3252 rac + −

3253 3254 3255 rac + −

3256 3257 3258 rac + −

3259 3260 3261 rac + −

3262 3263 3264 rac + −

3265 3266 3267 rac + −

3268 3269 3270 rac + −

3271 3272 3273 rac + −

3274 3275 3276 rac + −

3277 3278 3279 rac + −

3280 3281 3282 rac + −

3283 3284 3285 rac + −

3286 3287 3288 rac + −

3289 3290 3291 rac + −

3292 3293 3294 rac + −

3295 3296 3297 rac + −

3298 3299 3300 rac + −

3301 3302 3303 rac + −

3304 3305 3306 rac + −

3307 3308 3309 rac + −

3310 3311 3312 rac + −

3313 3314 3315 rac + −

3316 3317 3318 rac + −

3319 3320 3321 rac + −

3322 3323 3324 rac + −

3325 3326 3327 rac + −

3328 3329 3330 rac + −

3331 3332 3333 rac + −

3334 3335 3336 rac + −

3337 3338 3339 rac + −

3340 3341 3342 rac + −

3343 3344 3345 rac + −

3346 3347 3348 rac + −

3349 3350 3351 rac + −

3352 3353 3354 rac + −

3355 3356 3357 rac + −

3358 3359 3360 rac + −

3361 3362 3363 rac + −

3364 3365 3366 rac + −

3367 3368 3369 rac + −

3370 3371 3372 rac + −

3373 3374 3375 rac + −

3376 3377 3378 rac + −

3379 3380 3381 rac + −

3382 3383 3384 rac + −

3385 3386 3387 rac + −

3388 3389 3390 rac + −

3391 3392 3393 rac + −

    No. Racemic or enantiomer     R3 3394 3395 3396 rac + −

3397 3398 3399 rac + −

3400 3401 3402 rac + −

3403 3404 3405 rac + −

3406 3407 3408 rac + −

3409 3410 3411 rac + −

3412 3413 3414 rac + −

3415 3416 3417 rac + −

3418 3419 3420 rac + −

3421 3422 3423 rac + −

3424 3425 3426 rac + −

3427 3428 3429 rac + −

3430 3431 3432 rac + −

3433 3434 3435 rac + −

3436 3437 3438 rac + −

3439 3440 3441 rac + −

3442 3443 3444 rac + −

3445 3446 3447 rac + −

3448 3449 3450 rac + −

3451 3452 3453 rac + −

3454 3455 3456 rac + −

3457 3458 3459 rac + −

3460 3461 3462 rac + −

3463 3464 3465 rac + −

3466 3467 3468 rac + −

3469 3470 3471 rac + −

3472 3473 3474 rac + −

3475 3476 3477 rac + −

3478 3479 3480 rac + −

3481 3482 3483 rac + −

3484 3485 3486 rac + −

3487 3488 3489 rac + −

3490 3491 3492 rac + −

3493 3494 3495 rac + −

3496 3497 3498 rac + −

3499 3500 3501 rac + −

3502 3503 3504 rac + −

3505 3506 3507 rac + −

3508 3509 3510 rac + −

3511 3512 3513 rac + −

3514 3515 3516 rac + −

3517 3518 3519 rac + −

3520 3521 3522 rac + −

3523 3524 3525 rac + −

3526 3527 3528 rac + −

3529 3530 3531 rac + −

3532 3533 3534 rac + −

3535 3536 3537 rac + −

3538 3539 3540 rac + −

3541 3542 3543 rac + −

3544 3545 3546 rac + −

3547 3548 3549 rac + −

3550 3551 3552 rac + −

3553 3554 3555 rac + −

3556 3557 3558 rac + −

3559 3560 3561 rac + −

3562 3563 3564 rac + −

3565 3566 3567 rac + −

3568 3569 3570 rac + −

3571 3572 3573 rac + −

3574 3575 3576 rac + −

3577 3578 3579 rac + −

3580 3581 3582 rac + −

3583 3584 3585 rac + −

3586 3587 3588 rac + −

3589 3590 3591 rac + −

3592 3593 3594 rac + −

3595 3596 3597 rac + −

3598 3599 3600 rac + −

3601 3602 3603 rac + −

3604 3605 3606 rac + −

3607 3608 3609 rac + −

3610 3611 3612 rac + −

3613 3614 3615 rac + −

3616 3617 3618 rac + −

3619 3620 3621 rac + −

3622 3623 3624 rac + −

3625 3626 3627 rac + −

3628 3629 3630 rac + −

3631 3632 3633 rac + −

3634 3635 3636 rac + −

3637 3638 3639 rac + −

3640 3641 3642 rac + −

3643 3644 3645 rac + −

3646 3647 3648 rac + −

3649 3650 3651 rac + −

3652 3653 3654 rac + −

    No. Racemic or enantiomer     R3 3655 3656 3657 rac + −

3658 3659 3660 rac + −

3661 3662 3663 rac + −

3664 3665 3666 rac + −

3667 3668 3669 rac + −

3670 3671 3672 rac + −

3673 3674 3675 rac + −

3676 3677 3678 rac + −

3679 3680 3681 rac + −

3682 3683 3684 rac + −

3685 3686 3687 rac + −

3688 3689 3690 rac + −

3691 3692 3693 rac + −

3694 3695 3696 rac + −

3697 3698 3699 rac + −

3700 3701 3702 rac + −

3703 3704 3705 rac + −

3706 3707 3708 rac + −

3709 3710 3711 rac + −

3712 3713 3714 rac + −

3715 3716 3717 rac + −

3718 3719 3720 rac + −

3721 3722 3723 rac + −

3724 3725 3726 rac + −

3727 3728 3729 rac + −

3730 3731 3732 rac + −

3733 3734 3735 rac + −

3736 3737 3738 rac + −

3739 3740 3741 rac + −

3742 3743 3744 rac + −

3745 3746 3747 rac + −

3748 3749 3750 rac + −

3751 3752 3753 rac + −

3754 3755 3756 rac + −

3757 3758 3759 rac + −

3760 3761 3762 rac + −

3763 3764 3765 rac + −

3766 3767 3768 rac + −

3769 3770 3771 rac + −

3772 3773 3774 rac + −

3775 3776 3777 rac + −

3778 3779 3780 rac + −

3781 3782 3783 rac + −

3784 3785 3786 rac + −

3787 3788 3789 rac + −

3790 3791 3792 rac + −

3793 3794 3795 rac + −

3796 3797 3798 rac + −

3799 3800 3801 rac + −

3802 3803 3804 rac + −

3805 3806 3807 rac + −

3808 3809 3810 rac + −

3811 3812 3813 rac + −

3814 3815 3816 rac + −

3817 3818 3819 rac + −

3820 3821 3822 rac + −

3823 3824 3825 rac + −

3826 3827 3828 rac + −

3829 3830 3831 rac + −

3832 3833 3834 rac + −

3835 3836 3837 rac + −

3838 3839 3840 rac + −

3841 3842 3843 rac + −

3844 3845 3846 rac + −

3847 3848 3849 rac + −

3850 3851 3852 rac + −

3853 3854 3855 rac + −

3856 3857 3858 rac + −

3859 3860 3861 rac + −

3862 3863 3864 rac + −

3865 3866 3867 rac + −

3868 3869 3870 rac + −

3871 3872 3873 rac + −

3874 3875 3876 rac + −

3877 3878 3879 rac + −

3880 3881 3882 rac + −

3883 3884 3885 rac + −

3886 3887 3888 rac + −

3889 3890 3891 rac + −

3892 3893 3894 rac + −

3895 3896 3897 rac + −

3898 3899 3900 rac + −

3901 3902 3903 rac + −

3904 3905 3906 rac + −

3907 3908 3909 rac + −

3910 3911 3912 rac + −

3913 3914 3915 rac + −

    No. racemic or enantiomer or stereoisomer     structure 3916 3917 3918 rac + −

3919   3920 3921 3922 3923 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

3924 3925 3926 rac + −

3927 3928 3929 rac + −

3930 3931 3932 rac + −

3933 3934 3935 rac + −

3936 3937 3938 rac + −

3939 3940 3941 rac + −

3942 3943 3944 rac + −

3945 3946 3947 rac + −

3948 3949 3950 rac + −

3951 3952 3953 rac + −

3954 3955 3956 rac + −

3957 3958 3959 rac + −

3960 3961 3962 rac + −

3963 3964 3965 rac + −

3966   3967 3968 3969 3970 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

3971 3972 3973 rac + −

3974 3975 3976 rac + −

3977 3978 3979 rac + −

3980 3981 3982 rac + −

3983 3984 3985 rac + −

3986 3987 3988 rac + −

3989 3990 3991 rac + −

3992 3993 3994 rac + −

3995 3996 3997 rac + −

3998   3999 4000 4001 4002 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4003 4004 4005 rac + −

4006 4007 4008 rac + −

4009 4010 4011 rac + −

4012 4013 4014 rac + −

4015 4016 4017 rac + −

4018 4019 4020 rac + −

4021 4022 4023 rac + −

4024 4025 4026 rac + −

4027 4028 4029 rac + −

4030 4031 4032 rac + −

4033 4034 4035 rac + −

4036 4037 4038 rac + −

4039 4040 4041 rac + −

4042 4043 4044 rac + −

4045 4046 4047 rac + −

4048 4049 4050 rac + −

4051 4052 4053 rac + −

4054 4055 4056 rac + −

4057 4058 4059 rac + −

4060 4061 4062 rac + −

4063 4064 4065 rac + −

4066 4067 4068 rac + −

4069 4070 4071 rac + −

4072 4073 4074 rac + −

4075 4076 4077 rac + −

4078 4079 4080 rac + −

4081 4082 4083 rac + −

4084 4085 4086 rac + −

4087 4088 4089 rac + −

4090 4091 4092 rac + −

4093 4094 4095 rac + −

4096 4097 4098 rac + −

4099 4100 4101 rac + −

4102 4103 4104 rac + −

4105 4106 4107 rac + −

4108 4109 4110 rac + −

4111 4112 4113 rac + −

4114 4115 4116 rac + −

4117 4118 4119 rac + −

4120 4121 4122 rac + −

4123 4124 4125 rac + −

4126 4127 4128 rac + −

4129 4130 4131 rac + −

4132 4133 4134 rac + −

4135 4136 4137 rac + −

4138 4139 4140 rac + −

4141 4142 4143 rac + −

4144 4145 4146 rac + −

4147 4148 4149 rac + −

4150 4151 4152 rac + −

4153 4154 4155 rac + −

4156 4157 4158 rac + −

4159 4160 4161 rac + −

4162 4163 4164 rac + −

4165 4166 4167 rac + −

4168 4169 4170 rac + −

4171 4172 4173 rac + −

4174 4175 4176 rac + −

4177 4178 4179 rac + −

4180 4181 4182 rac + −

4183 4184 4185 rac + −

4186 4187 4188 rac + −

4189 4190 4191 rac + −

4192 4193 4194 rac + −

4195 4196 4197 rac + −

4198 4199 4200 rac + −

4201 4202 4203 rac + −

4204 4205 4206 rac + −

4207 4208 4209 rac + −

4210 4211 4212 rac + −

4213 4214 4215 rac + −

4216 4217 4218 rac + −

4219 4220 4221 rac + −

4222 4223 4224 rac + −

4225 4226 4227 rac + −

4228 4229 4230 rac + −

4231 4232 4233 rac + −

4234 4235 4236 rac + −

4237 4238 4239 rac + −

4240 4241 4242 rac + −

4243 4244 4245 rac + −

4246 4247 4248 rac + −

4249 4250 4251 rac + −

4252 4253 4254 rac + −

4255 4256 4257 rac + −

4258 4259 4260 rac + −

4261 4262 4263 rac + −

4264 4265 4266 rac + −

4267 4268 4269 rac + −

4270 4271 4272 rac + −

4273 4274 4275 rac + −

4276 4277 4278 rac + −

4279 4280 4281 rac + −

4282 4283 4284 rac + −

4285   4286 4287 4288 4289 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4290   4291 4292 4293 4294 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4295 4296 4297 rac + −

4298 4299 4300 rac + −

4301   4302 4303 4304 4305 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4306 4307 4308 rac + −

4309 4310 4311 rac + −

4312 4313 4314 rac + −

4315 4316 4317 rac + −

4318 4319 4320 rac + −

4321 4322 4323 rac + −

4324 4325 4326 rac + −

4327 4328 4329 rac + −

4330 4331 4332 rac + −

4333 4334 4335 rac + −

4336 4337 4338 rac + −

4339 4340 4341 rac + −

4342 4343 4344 rac + −

4345 4346 4347 rac + −

4348 4349 4350 rac + −

4351 4352 4353 rac + −

4354 4355 4356 rac + −

4357 4358 4359 rac + −

4360 4361 4362 rac + −

4363 4364 4365 rac + −

4366 4367 4368 rac + −

4369   4370 4371 4372 4373 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4374 4375 4376 rac + −

4377 4378 4379 rac + −

4380 4381 4382 rac + −

4383 4384 4385 rac + −

4386 4387 4388 rac + −

4389 4390 4391 rac + −

4392 4393 4394 rac + −

4395 4396 4397 rac + −

4398 4399 4400 rac + −

4401 4402 4403 rac + −

4404 4405 4406 rac + −

4407 4408 4409 rac + −

4410 4411 4412 rac + −

4413 4414 4415 rac + −

4416 4417 4418 rac + −

4419 4420 4421 rac + −

4422 4423 4424 rac + −

4425 4426 4427 rac + −

4428 4429 4430 rac + −

4431 4432 4433 rac + −

4434   4435 4436 4437 4438 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4439 4440 4441 rac + −

4442 4443 4444 rac + −

4445 4446 4447 rac + −

4448 4449 4450 rac + −

4451 4452 4453 rac + −

4454 4455 4456 rac + −

4457 4458 4459 rac + −

4460 4461 4462 rac + −

4463 4464 4465 rac + −

4466 4467 4468 rac + −

4469   4470 4471 4472 4473 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4474   4475 4476 4477 4478 4479 4480 4481 4482 stereoisomer mixture (R, R, R) (S, S, S) (R, R, S) (R, S, S) (R, S, R) (S, S, R) (S, R, R) (S, R, S)

4483   4484 4485 4486 4487 stereoisomer mixture (R, R) (S, S) (R, S) (S, R)

4488 4489 4490 rac + −

4491 4492 4493 rac + −


14. Pharmaceutical composition comprising at least one compound of the general formula I according to any of claims 1 to 12 and, where appropriate, at least one further active ingredient together with pharmaceutically suitable excipients and/or carriers.
 15. Pharmaceutical composition according to claim 14, where the further active ingredient is a SERM (selective oestrogen receptor modulator), an aromatase inhibitor, antioestrogen or a prostaglandin.
 16. Pharmaceutical composition according to claim 15, where the further active ingredients may be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9-(4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-7alpha-{5-[methyl(7,7,8,8,9,9,10,10,10-nonafluorodecyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9-pentafluorononyl)amino]pentyl}estra-1,3,5(10)-triene-3,17beta-diol, clomifene, raloxifene, fadrozole, formestane, letrozole, anastrozole or atamestane.
 17. Compounds according to any of claims 1 to 13 for the manufacture of a medicament.
 18. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea.
 19. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of hormone-dependent tumours.
 20. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of breast carcinomas.
 21. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of endometrial carcinoma.
 22. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of ovarian carcinomas.
 23. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for the therapy and/or prophylaxis of prostate carcinomas.
 24. Use of compounds according to any of claims 1 to 13 for the manufacture of a medicament for female hormone replacement therapy.
 25. Use of compounds according to any of claims 1 to 13 for female fertility control. 